Pyrimidine derivatives as modulators of chemokine receptor activity

ABSTRACT

Compounds of formula (1), pharmaceutically acceptable salts, solvates and in vivo hydrolysable esters thereof, have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CXCR2) activity, and may be in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is national phase application under 35 U.S.C. § 371 ofPCT International Application No. PCT/GB2003/003632, filed Aug. 20,2003, which claims Priority to Great Britain Application Serial No.0219819.0, filed Aug. 24, 2002 and Great Britain Application Serial No.0223287.4, filed Oct. 8, 2002.

The present invention relates to certain heterocyclic compounds,processes and intermediates used in their preparation, pharmaceuticalcompositions containing them and their use in therapy.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. These small secreted molecules are a growingsuperfamily of 8-14 kDa proteins characterised by a conserved cysteinemotif. At the present time, the chemokine superfamily comprises threegroups exhibiting characteristic structural motifs, the C—X—C, C—C andC—X₃—C families. The C—X—C and C—C families have sequence similarity andare distinguished from one another on the basis of a single amino acidinsertion between the NH-proximal pair of cysteine residues. The C—X₃—Cfamily is distinguished from the other two families on the basis ofhaving a triple amino acid insertion between the NH-proximal pair ofcysteine residues.

The C—X—C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils. Examples include human monocytechemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated onActivation, Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

The C—X₃—C chemokine (also known as fractalkine) is a potentchemoattractant and activator of microglia in the central nervous system(CNS) as well as of monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for theC—X₃—C family. These receptors represent good targets for drugdevelopment since agents which modulate these receptors would be usefulin the treatment of disorders and diseases such as those mentionedabove.

The present invention provides compounds of formula (1),pharmaceutically acceptable salts or solvates thereof and in vivohydrolysable esters thereof:

wherein R¹ is a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; wherein the group is optionally substitutedby 1, 2 or 3 substituents independently selected from fluoro, nitrile,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, phenyl or heteroaryl; wherein phenyl and heteroaryl areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl;

-   wherein R² is C₃₋₇carbocyclyl, optionally substituted by 1, 2 or 3    substituents independently selected from:-   (a) fluoro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,    —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;-   (b) a 3-8 membered ring optionally containing 1, 2 or 3 atoms    selected from O, S, —NR⁸ and whereby the ring is optionally    substituted by C₁₋₃alkyl or fluoro; or-   (c) phenyl or heteroaryl, each of which is optionally substituted by    1, 2 or 3 substituents independently selected from halo, cyano,    nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹,    C₁₋₆alkyl and trifluoromethyl;-   or R² is a group selected from C₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl    wherein the group is substituted by 1, 2 or 3 substituents    independently selected from hydroxy, amino, C₁₋₆alkoxy,    C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-(phenyl)amino,    N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl,    —NR⁸COR⁹, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹;-   wherein R³ is hydrogen or R²;-   R⁴ is hydrogen or a group selected from C₁₋₆alkyl and phenyl,    wherein the group is optionally substituted by 1 or 2 substituents    independently selected from halo, phenyl, —OR¹¹ and —NR¹²R¹³;-   R⁵ and R⁶ are independently hydrogen or a group selected from    C₁₋₆alkyl and phenyl wherein the group is optionally substituted by    1, 2 or 3 substituents independently selected from halo, phenyl,    —OR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶ and NR¹⁵SO₂R¹⁶    or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    form a 4- to 7-membered saturated heterocyclic ring system    optionally containing a further heteroatom selected from oxygen and    nitrogen atoms, where the ring system may be optionally substituted    by 1, 2 or 3 substituents independently selected from phenyl, —OR¹⁴,    —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or    C₁₋₆alkyl (optionally substituted by 1 or 2 substituents    independently selected from halo, —NR¹⁵R¹⁶ and —OR¹⁷ groups);-   R¹⁰ is hydrogen or a group selected from C₁₋₆alkyl or phenyl,    wherein the group is optionally substituted by 1, 2 or 3    substituents independently selected from halo, phenyl, —OR¹⁷ and    —NR¹⁵R¹⁶; and-   each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶, R¹⁷ is    independently hydrogen, C₁₋₆alkyl or phenyl;-   X is hydrogen, halo, cyano, nitro, hydroxy, C₁₋₆alkoxy (optionally    substituted by 1 or 2 substituents selected from halo, —OR¹¹ and    —NR¹²R¹³), —NR⁵R⁶, —COOR⁷, —CONR⁵R⁶, —NR⁸COR⁹, thio, thiocyano,    thioC₁₋₆alkyl (optionally substituted by 1 or 2 substituents    selected from halo, —OR¹⁷, —CO₂R⁷, —NR¹⁵R¹⁶, —CONR⁵R⁶), —SO₂R¹⁰,    —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰ or a group selected from C₃₋₇carbocyclyl,    C₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, wherein the group is    optionally substituted by 1, 2 or 3 substituents independently    selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,    —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹; or a -phenyl, -heteroaryl,    -thiophenyl, -thioheteroaryl, aminoheteroaryl, and thioC₁₋₆    alkylheteroaryl group, all of which may be optionally substituted by    1, 2 or 3 substituents independently selected from halo, cyano,    nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,    —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl, phenyl, heteroaryl or    trifluoromethyl groups.

Certain compounds of formula (1) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (1) and mixtures thereof including racemates.

The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, the above-mentioned activity may be evaluatedusing the standard laboratory techniques referred to hereinafter.

Within the present invention it is to be understood that a compound offormula (1) or a salt, solvate or in vivo hydrolysable ester thereof mayexhibit the phenomenon of tautomerism and that the formulae drawingswithin this specification can represent only one of the possibletautomeric forms. It is to be understood that the invention encompassesany tautomeric form and mixtures thereof and is not to be limited merelyto any one tautomeric form utilised within the formulae drawings. Theformulae drawings within this specification can represent only one ofthe possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It is also to be understood that certain compounds of formula (1) andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms.

The present invention relates to the compounds of formula (1) ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula (1) and their pharmaceutically acceptable salts.Pharmaceutically acceptable salts of the invention may, for example,include acid addition salts of the compounds of formula (1) ashereinbefore defined which are sufficiently basic to form such salts.Such acid addition salts include for example salts with inorganic ororganic acids affording pharmaceutically acceptable anions such as withhydrogen halides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid.Suitable salts include hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates,lactates, tartrates, oxalates, methanesulphonates orp-toluenesulphonates. Pharmaceutically acceptable salts of the inventionmay also include basic addition salts of the compounds of formula (1) ashereinbefore defined which are sufficiently acidic to form such salts.Such salts may be formed with an inorganic or organic base which affordsa pharmaceutically acceptable cation. Such salts with inorganic ororganic bases include for example an alkali metal salt, such as alithium, sodium or potassium salt, an alkaline earth metal salt such asa calcium or magnesium salt, an ammonium salt or an organic amine salt,for example a salt with methylamine, dimethylamine, trimethylamine,triethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.Other basic addition salts include aluminium, zinc, benzathine,chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine,meglumine, tromethamine or procaine.

The present invention further relates to an in vivo hydrolysable esterof a compound of formula (1). An in vivo hydrolysable ester of acompound of formula (1) which contains carboxy or hydroxy group is, forexample a pharmaceutically acceptable ester which is cleaved in thehuman or animal body to produce the parent acid or alcohol. Such esterscan be identified by administering, for example, intravenously to a testanimal, the compound under test and subsequently examining the testanimal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically-acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection ofin-vivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example acetyl; benzoyl; phenylacetyl; substitutedbenzoyl and phenylacetyl, C₁₋₁₀alkoxycarbonyl (to give alkyl carbonateesters), for example ethoxycarbonyl; di-(C₁₋₄)alkylcarbamoyl andN-(di-(C₁₋₄)alkylaminoethyl)-N—(C₁₋₄)alkylcarbamoyl (to givecarbamates); di-(C₁₋₄)alkylaminoacetyl and carboxyacetyl. Examples ofring substituents on phenylacetyl and benzoyl include aminomethyl,(C₁₋₄)alkylaminomethyl and di-((C₁₋₄)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring. Other interestingin-vivo hyrolysable esters include, for example,R^(A)C(O)O(C₁₋₆)alkyl-CO—, wherein R^(A) is for example,benzyloxy-(C₁₋₄)alkyl, or phenyl). Suitable substituents on a phenylgroup in such esters include, for example,4-(C₁₋₄)piperazino-(C₁₋₄)alkyl, piperazino-(C₁₋₄)alkyl andmorpholino-(C₁₋₄)alkyl.

In this specification the term “alkyl” includes both straight-chain andbranched-chain alkyl groups. However references to individual alkylgroups such as “propyl” are specific for the straight chain version onlyand references to individual branched-chain alkyl groups such as t-butylare specific for the branched chain version only. For example,“C₁₋₃alkyl” includes methyl, ethyl, propyl and isopropyl and examples of“C₁₋₆alkyl” include the examples of “C₁₋₃alkyl” and additionallyt-butyl, pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl. Examplesof “C₁₋₈alkyl” include the examples of “C₁₋₆alkyl” and additionallyheptyl, 2,3-dimethylpentyl, 1-propylbutyl and octyl. An analogousconvention applies to other terms, for example “C₂₋₆alkenyl” includesvinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methylbut-1-enyl,1-pentenyl and 4-hexenyl and examples of “C₂₋₆alkynyl” includes ethynyl,1-propynyl, 3-butynyl, 2-pentynyl and 1-methylpent-2-ynyl.

“C₃₋₇carbocyclyl” is a saturated, partially saturated or unsaturated,monocyclic ring containing 3 to 7 carbon ring atoms wherein a —CH₂—group can optionally be replaced by a —C(O)—. Suitable examples of“carbocyclyl” are cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,cyclohexenyl, 4-oxocyclohex-1-yl and 3-oxocyclohept-5-en-1-yl.

The term “halo” refers to fluoro, chloro, bromo and iodo.

Examples of “C₁₋₆alkoxy” include methoxy, ethoxy, propoxy, isopropoxy,butyloxy, pentyloxy, 1-ethylpropoxy and hexyloxy. Examples of“C₁₋₆alkylamino” include methylamino, ethylamino, propylamino,butylamino and 2-methylpropylmino. Examples of “di(C₁₋₆alkyl)amino”include dimethylamino, N-methyl-N-ethylamino, diethylamino,N-propyl-N-3-methylbutylamino. Examples of“N—(C₁₋₆alkyl)-N-(phenyl)amino” include N-methyl-N-phenylamino,N-propyl-N-phenylamino and N-(2-methylbutyl)-N-phenylamino. Examples of“N—(C₁₋₆alkyl)carbamoyl” are N-methylcarbamoyl, N-ethylcarbamoyl andN-(2-ethylbutylcarbamoyl. Examples of“N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl” include N-methyl-N-phenylcarbamoyl,N-butyl-N-phenylcarbamoyl and N-(3-methylpentyl)-N-(phenyl)carbamoyl.Examples of “N,N-di(C₁₋₆alkyl)carbamoyl” include N,N-dimethylcarbamoyl,N-methyl-N-ethylcarbamoyl and N-propyl-N-(2-methylbutyl)carbamoyl.Examples of “thioC₁₋₆alkyl” include -thiomethyl, -thioethyl,-thiopropyl, -thiobutyl and -thio-2-methylbutyl.

“Heteroaryl” is monocyclic or bicyclic aryl ring containing 5 to 10 ringatoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphuror oxygen. Examples of heteroaryl include pyrrolyl, furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, thiopyridone,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzfuranyl, benzthieno,indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl,benzisoxazolyl, benzisothiazolyl, benztriazolyl, quinolinyl,isoquinolinyl and naphthiridinyl.

Examples of “a 3-8 membered ring optionally containing 1, 2 or 3 atomsselected from O, S and NR⁸” include azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl,piperazinyl and morpholinyl.

Examples of “a 4- to 7-membered saturated heterocyclic ring system”include azetidinlyl, pyrrolidihyl, piperidinyl, piperazinyl,homopiperazinyl and morpholinyl.

Where optional substituents are chosen from “1, 2 or 3” groups it is tobe understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups. An analogous conventionapplies to substituents chosen from “1 or 2” groups.

Convenient values of R¹, R², R³ and X are as follows. Such values may beused where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

In one aspect of the present invention there is provided a compound offormula (1) as depicted above wherein R¹ is C₁₋₈alkyl optionallysubstituted by 1, 2 or 3 substituents independently selected from phenylor heteroaryl, wherein phenyl and heteroaryl are optionally substitutedby 1, 2 or 3 substituents independently selected from halo, cyano, —OR⁴,—SR¹⁰, C₁₋₆alkyl and trifluoromethyl.

In another aspect of the invention R¹ is benzyl optionally substitutedby 1 or 2 substituents independently selected from fluoro, chloro,bromo, methoxy, methyl and trifluoromethyl.

In one aspect of the invention R² is C₁₋₈alkyl substituted by 1, 2 or 3substituents independently selected from hydroxy, amino, C₁₋₆alkoxy,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-(phenyl)amino,N—C₁₋₆alkylcarbamoyl, N,N-di(C₁₋₆alkyl)carbamoyl,N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl, —NR⁸COR⁹,—SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹.

In another aspect R² is C₁₋₈alkyl, such as C₁₋₄alkyl, substituted by 1,2 or 3 substituents independently selected from hydroxy, amino,C₁₋₆alkoxy, C₁₋₆alkylamino, and di(C₁₋₆alkyl)amino.

In another aspect R² is C₁₋₄alkyl substituted by hydroxy.

In a further aspect R² is 2-hydroxy-1-methylethyl.

In one aspect of the invention R³ is hydrogen.

In one aspect of the invention R⁴ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention R⁵ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention R⁶ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention R¹⁰ is hydrogen, C₁₋₄alkyl or phenyl.

In one aspect of the invention X is hydrogen, halo, cyano, nitro,hydroxy, —NR⁵R⁶, thio, thiocyano, —CONR⁵R⁶, thioC₁₋₆alkyl (optionallysubstituted by 1 or 2 substituents selected from halo, —OR¹⁷, —CONR⁵R⁶,—COOR⁷, —NR¹⁵R¹⁶), —NR⁸SO₂R¹⁰, C₁₋₈alkyl (optionally substituted by 1, 2or 3 substituents independently selected from halo, —OR⁴, —NR⁵R⁶,—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹) ora -phenyl, -heteroaryl, -thiophenyl, -thioheteroaryl, aminoheteroaryl,and thioC₁₋₆alkylheteroaryl group, all of which may be optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆alkyl, phenyl, heteroaryl or trifluoromethylgroups;

In another aspect X is hydrogen, halo, cyano, nitro, hydroxy, thio,thiocyano, —CONR⁵R⁶, thioC₁₋₆alkyl (optionally substituted by 1 or 2substituents selected from halo, —OR¹⁷, —NR¹⁵R¹⁶, —CONR⁵R⁶), —NR⁸SO₂R¹⁰,C₁₋₈alkyl (optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷,—NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹), heteroaryl,thioheteroaryl or thioC₁₋₆alkylheteroaryl all of which may be optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl or trifluoromethyl.

In another aspect X is hydrogen.

In another aspect X is —CONR⁵R⁶

In another aspect X is 1,2,4-oxadiazol-3-ylmethanethio

In another aspect X is NR⁸SO₂R¹⁰ where R⁸ is hydrogen and R⁹ is methyl.

In another aspect X is thiocyano.

In another aspect X is thiothiadazolyl, thioimidazolyl or thiotriazolyl.

In a further aspect X is fluoro, chloro or cyano

A particular class of compound is of formula (1) wherein;

-   R¹ is C₁₋₈alkyl optionally substituted by 1, 2 or 3 substituents    independently selected from phenyl or heteroaryl, wherein phenyl and    heteroaryl are optionally substituted by 1, 2 or 3 substituents    independently selected from halo, cyano, —OR⁴, —SR¹⁰, C₁₋₆alkyl and    trifluoromethyl;-   R² is C₁₋₈alkyl substituted by 1, 2 or 3 substituents independently    selected from hydroxy, amino, C₁₋₆alkoxy, C₁₋₆alkylamino,    di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-phenyl)amino,    N—C₁₋₆alkylcarbamoyl, N,N-di(C₁₋₆alkyl)carbamoyl,    N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl,    —NR⁸COR⁹, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹;-   R³ is hydrogen;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶ and R¹⁷ are    independently hydrogen, C₁₋₄alkyl or phenyl; and-   X is halo, cyano, nitro, hydroxy, thio, —NR⁵R⁶, thiocyano, —CONR⁵R⁶,    thioC₁₋₆alkyl (optionally substituted by 1 or 2 substituents    selected from halo, —OR¹⁷, —NR¹⁵R¹⁶, —CONR⁵R⁶), —NR⁸SO₂R¹⁰,    C₁₋₈alkyl (optionally substituted by 1, 2 or 3 substituents    independently selected from halo, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷,    —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹);-   or an aryl, heteroaryl, thioheteroaryl or thioC₁₋₆alkylheteroaryl    all of which may be optionally substituted by 1, 2 or 3 substituents    independently selected from halo, cyano, nitro, —OR⁴, —NR⁵R⁶,    —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹,    C₁₋₆alkyl or trifluoromethyl;

A preferred class of compound is of formula (1) wherein;

-   R¹ is benzyl optionally substituted by 1 or 2 substituents    independently selected from fluoro and chloro;-   R² is C₁₋₄alkyl substituted by hydroxy;-   R³ is hydrogen;-   X is fluoro, chloro, cyano or thioimidazolyl.

Compounds of the invention include:

-   2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol-   2-(Benzylthio)-5-chloro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol-   2-[(3-Chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol-   5-Chloro-2-[(3-chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol-   2-[(3-Chlorobenzyl)thio]-4-hydroxy-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-pyrimidinyl    thiocyanate-   N-(2-[(3-Chlorobenzyl)thio]-4-hydroxy-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-pyrimidinyl)methanesulfonamide-   2-[(3-Chlorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol-   2-[(2,3-difluorobenzyl)thio]-4-hydroxy-6{[(1S)-2-hdroxy-1-methylethyl]amino}pyrimidine-5-carbonitrile-   5-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-iodo-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitro-4-pyrimidinol,-   2-[[(3-Chlorophenyl)methyl]thio]-6-[[(1R)2-hydroxy-1-methylethyl]amino]-5-(1,3,4-thiadiazol-2-ylthio)-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1H-imidazol-2-ylthio)-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-5-[[2-(dimethylamino)ethyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol,-   1-[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]-4(1H)-pyridinethione,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(4-pyridinylthio)-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1H-1,2,4-triazol-3-ylthio)-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-4-pyrimidinol,-   5-[(5-Amino-4H-1,2,4-triazol-3-yl)thio]-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[[5-(4-pyridinyl)-1,3,4-oxadiazol-2-yl]thio]-4-pyrimidinol,-   Ethyl[[2-[[(2,3-difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy    1-methylethyl]amino]-5-pyrimidinyl]thio]-AcOH,-   2-[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-N-methyl-acetamide,-   2-[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-N-[2-(dimethylamino)ethyl]-acetamide,-   1-[[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]acetyl]-piperazine,-   -[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(4-methyl-2-oxazolyl)thio]-4-pyrimidinol,-   2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(1,2,4-oxadiazol-3-ylmethyl)thio]-4-pyrimidinol,-   2-[(2,3-difluorobenzyl)thio]-4-{[(1R)-1,2-dihydroxyethyl]amino}-6-hydroxypyrimidine-5-carboxamide,-   2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-ol,-   2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-(1,3-oxazol-5-yl)pyrimidin-4-ol,-   2-[(2,3-difluorobenzyl)thio]-4-{[(1R)-1,2-dihydroxyethyl]amino}-6-hydroxy-N,N-dimethylpyrimidine-5-carboxamide,-   2-[(2,3-difluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-ol,-   2-[(3,4-difluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-ol,-   2-[(3-fluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol,    or-   2-[(4-fluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol    and pharmaceutically acceptable salts, solvates or in vivo    hydrolysable esters thereof.

Each of the above mentioned compounds and the pharmaceuticallyacceptable salts, solvates or in vivo hydrolysable esters thereof,individually is a preferred aspect of the invention.

The present invention further provides four processes for thepreparation of compounds of formula (1) as defined above which comprise:

Process 1

a) treating a compound of formula (2):

wherein R¹, R² and R³ are as defined in formula (1), with suitableelectrophiles.and optionally thereafter (i), (ii), (iii), (iv) or (v) in any order:

-   i) removing any protecting groups;-   ii) converting the compound of formula (1) into a further compound    of formula (1),-   iii) forming a salt;-   (iv) forming a prodrug,-   v) forming an in vivo hydrolysable ester

Reaction of compounds of formula (2) wherein R¹, R² and R³ are asdefined in formula (1), with suitable electrophiles include thefollowing representative examples: fluorination (Selectfluor™ inmethanol) or chlorination, bromination or iodination(N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, all inacetic acid), or chlorination (sulfulyl chloride) or bromination(bromine in N,N-diethylformamide) or thiocyanation (by in situ reactionwith bromine and potassium thiocyanate) or nitrosation (sodium nitritein acetic acid) or nitration (nitronium tetrafluoroborate in sulfolane)or electrophilic substitution with sulfenyl halides (alkyl-, aryl- orheteroarylthiols, bromine and pyridine in N,N-dimethylformamide).Further compounds of formula (1) can then be obtained by reduction ofthe nitro or nitroso compounds to the amine (zinc in acetic acid) andsubsequent treatment with either sulfonyl chlorides or acid chlorides toyield compounds of formula (1) where X is alkyl-, aryl- orheteroarylsulfonamido- and alkyl-, aryl- or heteroarylamido-respectively. Further reactions of the brominated or iodinated compoundswith aryl and heteroaryl boronic acids yield compounds of formula (1)where X is aryl or heteroaryl. Further reactions of the thiocyanatedproduct with sodium borohydride and then alkyl halides yield compoundsof formula (1) where X is -thioalkylaryl or -thioalkylheteroaryl.

Compounds of formula (2) wherein R¹, R² and R³ are as defined in formula(1), can be prepared from compounds of formula (3) wherein R² and R³ areas defined in formula (1) by treatment with alkyl halides R¹A, where R¹is as defined in formula (1) and A is a halogen, in he presence asuitable base and solvent.

Examples of suitable bases include the alkali metal hydroxides such asLi, Na, or K, or metal carbonates such as Li, Na, K or Cs, or metalacetates such as Li, Na, K or Cs, or metal alkoxides such as Li, Na,K-tert-butoxide. Suitable solvents include N,N-dimethylamides,1-methyl-2-pyrolidinone, ethers such as tetrahydrofuran, 1,4-dioxane,glyme and diglyme and alcohols such as methanol, ethanol andtert-butanol. Preferably potassium hydroxide in N,N-dimethylformamide atambient temperature is employed.

Compounds of formula (3) wherein R² and R³ are as defined in formula (1)may be prepared by reaction of 6-amino-2-mercapto-4-pyrimidinol withamines HNR²R³ where R² and R³ are as defined in formula (1) in thepresence of acetic acid at a temperature of 150-200° C.

Process 2

The present invention further provides a process for the preparation ofa compound of formula (1) as defined above, where X is 1,3-oxazol-5-ylby;

-   b) treating a compound of formula (4):

wherein R¹, R² and R³ are as defined in formula (1), X is —CHO and Y isprotected hydroxy by treatment with p-toluenesulfonylmethyl isocyanideand potassium hydroxide in refluxing methanol.

-   and optionally thereafter (i), (ii), (iii), (iv) or (v) in any    order:-   i) removing any protecting groups;-   ii) converting the compound of formula (1) into a further compound    of formula (1),-   iii) forming a salt;    -   (iv) forming a prodrug,    -   v) forming an in vivo hydrolysable ester

Compounds of formula (4) wherein R¹, R² and R³ are as defined in formula(1), X is —CHO and Y is protected hydroxy can be prepared from compoundsof formula (4) wherein R¹, R² and R³ are as defined in formula (1), X is—CHO and Y is halogen by treatment with allyl alcohol in the presence ofaqueous sodium hydroxide solution.

Compounds of formula (4) wherein R¹, R² and R³ are as defined in formula(1), X is —CHO and Y is halogen can be prepared from compounds offormula (5) wherein R¹ is as defined in formula (1), X is —CHO and Y ishalogen by treatment with amines R²R³NH in the presence a suitable baseand solvent.

Examples of suitable bases include trialkylamines, such as triethylamineor N,N-diisopropylethylamine. Suitable solvents includeN,N-diethylamides, 1-methyl-2-pyrolidone, and ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of thereaction can be performed between 0° C. and 100° C. Preferablytriethylamine in N,N-dimethylformamide at room temperature is used.

Compounds of formula (5) wherein R¹ is as defined in formula (1), X is—CHO and Y is halogen;

may be prepared by reaction of compounds of formula (6) wherein R¹ is asdefined in formula (1) with a halogenating agent such as phosphorousoxychloride in the presence of N,N-dimethylformamide.

Compounds of formula (6) wherein R¹ is as defined in formula (1) may beprepared by reaction of 4,6-dihydroxy-2-mercaptopyrimidine withalkylhalides R₁A where R₁ is as defined in formula (1) and A is halogenin the presence of a suitable base and solvent. Examples of suitablebases include the alkali metal hydroxides such as Li, Na, or K, or metalcarbonates such as Li, Na, K or Cs, or metal acetates such as Li, Na, Kor Cs, or metal alkoxides such as Li, Na, K-tert-butoxide. Suitablesolvents include N,N-diethylamides, 1-methyl-2-pyrolidinone, ethers suchas tetrahydrofuran, 1,4-dioxane, glyme and diglyme and alcohols such asmethanol, ethanol and tert-butanol. Preferably potassium hydroxide inN,N-dimethylformamide at ambient temperature is employed.

Process 3

The present invention further provides a process for the preparation ofa compound of formula (1) as defined above, where X is CN by,

-   b) treating a compound of formula (4):

wherein R¹, R² and R³ are as defined in formula (1), X is CN and Y ishalogen by treatment with potassium tert-butoxide in refluxing aqueoustoluene.

-   and optionally thereafter (i), (ii), (iii), (iv) or (v) in any    order:-   i) removing any protecting groups,-   ii) converting the compound of formula (1) into a further compound    of formula (1), for example treatment of a compound of formula (1)    as defined above, where X is CN with hydroxylamine hydrochloride and    sodium ethoxide and then acetic anhydride to provide a compound of    formula (1) as defined above, where X is    5-methyl-1,2,4-oxadiazol-3-yl;-   iii) forming a salt;-   (iv) forming a prodrug,-   v) forming an in vivo hydrolysable ester

Compounds of formula (4) wherein R¹, R² and R³ are as defined in formula(1), X is CN and Y is halogen can be prepared from compounds of formula(5) wherein R¹ is as defined in formula (1), X is CN and Y is halogen bytreatment with amines R²R³NH in the presence of a suitable base andsolvent.

Examples of suitable bases include trialkylamines, such as triethylamineor N,N-diisopropylethylamine. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidone, and ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of thereaction can be performed between 0° C. and 100° C. Preferablytriethylamine in N,N-dimethylformamide at room temperature is used.Compounds of formula (5) wherein R¹ is as defined in formula (1), X isCN and Y is halogen may be prepared by reaction of compounds of formula(5) wherein R¹ is as defined in formula (1) X is —CHO and Y is halogenwith hydroxylamine to form an oxime and subsequent dehydration with adehydrating agent such as thionyl chloride. Compounds of formula (5)wherein R¹ is as defined in formula (1), X is —CHO and Y is halogen maybe formed as described in Process (2).

Process 4

The present invention further provides a process for the preparation ofa compound of formula (1) as defined above, where X is —CONR⁵R⁶ by;

-   c) treating a compound of formula (4):

wherein R¹, R² and R³ are as defined in formula (1), X is —CONR⁵R⁶ and Yis halogen with a suitable base.

-   and optionally thereafter (i), (ii), (iii), (iv) or (v) in any    order:-   i) removing any protecting groups;-   ii) converting the compound of formula (1) into a further compound    of formula (1),-   iii) forming a salt;-   (iv) forming a prodrug,-   v) forming an in vivo hydrolysable ester

Examples of suitable bases include the alkali metal hydroxides such asLi, Na, or K, or metal carbonates such as Li, Na, K or Cs, or metalacetates such as Li, Na, K or Cs, or metal alkoxides such as Li, Na,K-tert-butoxide. Suitable solvents include N,N-dimethylamides,1-methyl-2-pyrolidinone, toluene, ethers such as tetrahydrofuran,1,4-dioxane, glyme and diglyme and alcohols such as methanol, ethanoland tert-butanol. Preferably potassium tert-butoxide in aqueous tolueneat 110° C. is used.

Compounds of formula (4) as defined above, where X is —CONR⁵R⁶ and Y ishalogen can be formed by treating a compound of formula (6):

wherein R² and R³ are as defined in formula (1), X is —CONR⁵R⁶ and Y ishalogen with a thiol R¹SH, wherein R¹ is as defined in formula (1), inthe presence of a suitable base. Examples of suitable bases include thetrialkylamines, such as triethylamine or N,N-diisopropylethylamine,alkali metal hydroxides such as Li, Na, or K, or metal carbonates suchas Li, Na, K or Cs, or metal acetates such as Li, Na, K or Cs, or metalalkoxides such as Li, Na, K-tert-butoxide. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidinone, ethers such astetrahydrofuran, 1,4-dioxane, glyme and diglyme and alcohols such asmethanol, ethanol and tert-butanol. Preferably triethylamine in methanolat ambient temperature is used.

Compounds of formula (6) wherein R² and R³ are as defined in formula(1), X is —CONR⁵R⁶ and Y is halogen can be prepared from compounds offormula (7);

wherein X is —CONR⁵R⁶ and Y is halogen by reacting with amines HNR²R³ inthe presence a suitable base and solvent.

Examples of suitable bases include the trialkylamines, such astriethylamine or N,N-diisopropylethylamine, alkali metal hydroxides suchas Li, Na, or K, or metal carbonates such as Li, Na, K or Cs, or metalacetates such as Li, Na, K or Cs, or metal alkoxides such as Li, Na,K-tert-butoxide. Suitable solvents include N,N-dimethylamides,1-methyl-2-pyrolidinone, ethers such as tetrahydrofuran, 1,4-dioxane,glyme and diglyme and alcohols such as methanol, ethanol andtert-butanol. Preferably triethylamine in N,N-dimethylformamide at −5°C. is used.

Compounds of formula (7) wherein X is —CONR⁵R⁶ and Y is halogen can beprepared from compounds of formula (7) wherein X is —COCl and Y ishalogen by reacting with amines HNR⁵R⁶ in the presence a suitable baseand solvent.

Examples of suitable bases include the trialkylamines, such astriethylamine or N,N-diisopropylethylamine. Suitable solvents includeN,N-dimethylamides, 1-methyl-2-pyrolidinone, dichloromethane, etherssuch as tetrahydrofuran, 1,4-dioxane, glyme and diglyme. Preferablysodium bicarbonate in dichloromethane at ambient temperature is used.Compounds of formula (7) wherein X is —COCl and Y is halogen can beprepared from compounds of formula (7) wherein X is —CHO and Y ishalogen by treatment with aza-bis-isobutyronitrile and sulfuryl chloridein dichloroethane at 50-80° C.

Compounds of formula (7) wherein X is —CHO and Y is halogen may beprepared by reaction of 2,4,6-trihydroxypyrimidine with a halogenatingagent such as phosphorous oxychloride in the presence ofN,N-dimethylformamide.

It will be appreciated by those skilled in the art that in the processdescribed above the functional groups of intermediates and startingcompounds may need to be protected by protecting groups as describedhereinbefore.

Compounds of formulae (2), (3), (4), (5), (6) and (7) are eithercommercially available, are well known in the literature or may beeasily prepared using known techniques.

A compound of formula (1) may be prepared from another compound offormula (1) by chemical modification. Examples of chemical modificationsinclude standard alkylation, arylation, heteroarylation, acylation,sulphonylation, phosphorylation, aromatic halogenation and couplingreactions. These reactions may be used to add new substituents or tomodify existing substituents. Alternatively, existing substituents incompounds of formula 1 may be modified by, for example, oxidation,reduction, elimination, hydrolysis or other cleavage reactions to yieldother compounds of formula (1).

The compounds of formula (1) above may be converted to apharmaceutically acceptable salt, solvate or in vivo hydrolysable esterthereof, as discussed above. The salt is preferably a basic additionsalt.

The compounds of formula (1) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CXCR2)activity, and may be used in the treatment (therapeutic or prophylactic)of conditions/diseases in human and non-human animals which areexacerbated or caused by excessive or unregulated production ofchemokines. Examples of such conditions/diseases include:

-   -   (1) (the respiratory tract) obstructive airways diseases        including chronic obstructive pulmonary disease (COPD); asthma,        such as bronchial, allergic, intrinsic, extrinsic and dust        asthma, particularly chronic or inveterate asthma (e.g. late        asthma and airways hyper-responsiveness); bronchitis; acute,        allergic, atrophic rhinitis and chronic rhinitis including        rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta,        rhinitis sicca and rhinitis medicamentosa; membranous rhinitis        including croupous, fibrinous and pseudomembranous rhinitis and        scrofoulous rhinitis; seasonal rhinitis including rhinitis        nervosa (hay fever) and vasomotor rhinitis; sarcoidosis,        farmer's lung and related diseases, fibroid lung and idiopathic        interstitial pneumonia;    -   (2) (bone and joints) rheumatoid arthritis, seronegative        spondyloarthropathies (including ankylosing spondylitis,        psoriatic arthritis and Reiter's disease), Behchet's disease,        Sjogren's syndrome and systemic sclerosis;    -   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis        and other eczmatous dermitides, seborrhoetic dermatitis, Lichen        planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,        urticaria, angiodermas, vasculitides, erythemas, cutaneous        eosinophilias, uveitis, Alopecia greata and vernal        conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, indeterminate colitis, microscopic colitis,        inflammatory bowel disease, irritable bowel syndrome,        non-inflammatory diarrhea, endometriosis, food-related allergies        which have effects remote from the gut, e.g., migraine, rhinitis        and eczema;    -   (5) (central and peripheral nervous system) Neurodegenerative        diseases and dementia disorders, e.g. Alzheimer's disease,        amyotrophic lateral sclerosis and other motor neuron diseases,        Creutzfeldt-Jacob's disease and other prion diseases, HIV        encephalopathy (AIDS dementia complex), Huntington's disease,        frontotemporal dementia, Lewy body dementia and vascular        dementia; polyneuropathies, e.g. Guillain-Barré syndrome,        chronic inflammatory demyelinating polyradiculoneuropathy,        multifocal motor neuropathy, plexopathies; CNS demyelination,        e.g. multiple sclerosis, acute disseminated/haemorrhagic        encephalomyelitis, and subacute sclerosing panencephalitis;        neuromuscular disorders, e.g. myasthenia gravis and        Lambert-Eaton syndrome; spinal disorders, e.g. tropical spastic        paraparesis, and stiff-man syndrome: paraneoplastic syndromes,        e.g. cerebellar degeneration and encephalomyelitis; CNS trauma;        migraine; and stroke.    -   (6) (other tissues and systemic disease) atherosclerosis,        Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus,        systemic lupus, erythematosus, Hashimoto's thyroiditis, type I        diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE        syndrome, lepromatous leprosy, and idiopathic thrombocytopenia        pupura; post-operative adhesions, and sepsis.    -   (7) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (8) Cancers, especially non-small cell lung cancer (NSCLC),        malignant melanoma, prostate cancer and squamous sarcoma, and        tumour metastasis, non melanoma skin cancer and chemoprevention        metastases;    -   (9) Diseases in which angiogenesis is associated with raised        CXCR2 chemokine levels (e.g. NSCLC, diabetic retinopathy);    -   (10) Cystic fibrosis;    -   (11) Bum wounds & chronic skin ulcers;    -   (12) Reproductive Diseases (e.g. Disorders of ovulation,        menstruation and implantation, Pre-term labour, Endometriosis);    -   (13) Re-perfusion injury in the heart, brain, peripheral limbs        and other organs, inhibition of atherosclerosis.

Thus, the present invention provides a compound of formula (1), or apharmaceutically-acceptable salt, solvate or an in vivo hydrolysableester thereof, as hereinbefore defined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CXC chemoline receptorsubfamily, more preferably the target chemokine receptor is the CXCR2receptor.

Particular conditions which can be treated with the compounds of theinvention are cancer, diseases in which angiogenesis is associated withraised CXCR2 chemokine levels, and inflammatory diseases such as asthma,allergic rhinitis, COPD, rheumatoid arthritis, psoriasis, inflammatorybowel diseases, osteoarthritis or osteoporosis.

As a further aspect of the present invention, certain compounds offormula (1) may have utility as antagonists of the CX3CR1 receptor. Suchcompounds are expected to be particularly useful in the treatment ofdisorders within the central and peripheral nervous system and otherconditions characterized by an activation of microglia and/orinfiltration of leukocytes (e.g. stroke/ischemia and head trauma).

In a further aspect, the present invention provides a compound offormula (1), or a pharmaceutically acceptable salt, solvate or in vivohydrolysable ester thereof, as hereinbefore defined for use as amedicament.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined for useas a medicament for the treatment of human diseases or conditions inwhich modulation of chemokine receptor activity is beneficial.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined for useas a medicament for the treatment of asthma, allergic rhinitis, cancer,COPD, rheumatoid arthritis, psoriasis, inflammatory bowel diseases,osteoarthritis or osteoporosis.

In a further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined in themanufacture of a medicament for use in therapy.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined in themanufacture of a medicament for the treatment of human diseases orconditions in which modulation of chemokine receptor activity isbeneficial.

In a still further aspect, the present invention provides the use of acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined in themanufacture of a medicament for the treatment of asthma, allergicrhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatorybowel diseases, osteoarthritis or osteoporosis.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating a chemokinemediated disease wherein the chemokine binds to a chemokine (especiallyCXCR2) receptor, which comprises administering to a patient atherapeutically effective amount of a compound of formula, or apharmaceutically acceptable salt, solvate or in vivo hydrolysable ester,as hereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially asthma, allergic rhinitis, COPD, rheumatoidarthritis, psoriasis, inflammatory bowel diseases, osteoarthritis orosteoporosis, in a patient suffering from, or at risk of, said disease,which comprises administering to the patient a therapeutically effectiveamount of a compound of formula (1), or a pharmaceutically acceptablesalt, solvate or in vivo hydrolysable ester thereof, as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (1) and pharmaceutically acceptable salts,solvates or in vivo hydrolysable esters thereof may be used on their ownbut will generally be administered in the form of a pharmaceuticalcomposition in which formula (1) compound/salt/solvate/ester (activeingredient) is in association with a pharmaceutically acceptableadjuvant, diluent or carrier. Depending on the mode of administration,the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.05 to 80% w, still morepreferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on totalcomposition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (1), or a pharmaceutically acceptablesalt, solvate or in vivo hydrolysable ester thereof, as hereinbeforedefined, in association with a pharmaceutically acceptable adjuvant,diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (1), or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, as hereinbefore defined, with apharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Preferably the compounds of the invention areadministered orally.

In addition to their use as therapeutic medicines, the compounds offormula (1) and their pharmaceutically acceptable salts, solvate or invivo hydrolysable esters are also useful as pharmacological tools in thedevelopment and standardisation of in vitro and in vivo test systems forthe evaluation of the effect of chemokine modulation activity inlaboratory animals such as cats, dogs, rabbits, monkeys, rats and mice,as part of the search for new therapeutic agents.

The invention further relates to combination therapies wherein acompound of formula (1) or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, or a pharmaceutical compositionor formulation comprising a compound of formula (1) is administeredconcurrently or sequentially with therapy and/or an agent for thetreatment of any one of asthma, allergic rhinitis, cancer, COPD,rheumatoid arthritis, psoriasis, inflammatory bowel disease, irritablebowel syndrome, osteoarthritis or osteoporosis.

In particular, for the treatment of the inflammatory diseases rheumatoidarthritis, psoriasis, inflammatory bowel disease, irritable bowelsyndrome, COPD, asthma and allergic rhinitis the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies (such as Remicade, CDP-870 andD.sub2.E.sub7.) and TNF receptor immunoglobulin molecules (such asEnbrel.reg.), non-selective COX-1/COX-2 inhibitors (such as piroxicam,diciofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin), COX-2 inhibitors (such as meloxicam,celecoxib, rofecoxib, valdecoxib and etoricoxib) low dose methotrexate,lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofinor parenteral or oral gold. For inflammatory bowel disease and irritablebowel disorder further convenient agents include sulphasalazine and5-ASAs, topical and systemic steroids, immunomodulators andimmunosuppressants, antibiotics, probiotics and anti-integrins.

The present invention still further relates to the combination of acompound of the invention together with a leukotriene biosynthesisinhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activatingprotein (FLAP) antagonist such as zileuton; ABT-761; fenleuton;tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinoline compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to the combination of acompound of the invention together with a receptor antagonist forleukotrienes LTB.sub4., LTC.sub4., LTD.sub4., and LTE.sub4. selectedfrom the group consisting of the phenothiazin-3-ones such as L-651,392;amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention together with a PDE4 inhibitor includinginhibitors of the isoform PDE4D.

The present invention still further relates to the combination of acompound of the invention together with a antihistaminic H.sub1.receptor antagonists such as cetirizine, loratadine, desloratadine,fexofenadine, astemizole, azelastine, and chlorpheniramine.

The present invention still further relates to the combination of acompound of the invention together with a gastroprotective H.sub2.receptor antagonist.

The present invention still further relates to the combination of acompound of the invention together with an α.sub1.- andα.sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, suchas propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, and ethylnorepinephrinehydrochloride.

The present invention still further relates to the combination of acompound of the invention together with anticholinergic agents such asipratropium bromide; tiotropium bromide; oxitropium bromide;pirenzepine; and telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a β.sub1.- toβ.sub4.-adrenoceptor agonists such as metaproterenol, isoproterenol,isoprenaline, albuterol, salbutamol, formoterol, salmeterol,terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; ormethylxanthanines including theophylline and aminophylline; sodiumcromoglycate; or muscarinic receptor (M1, M2, and M3) antagonist.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention together with an inhaled glucocorticoid withreduced systemic side effects, such as prednisone, prednisolone,flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, and mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-12.

The present invention still further relates to the combination of acompound of the invention together with other modulators of chemokinereceptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for the C—X₃—Cfamily.

The present invention still further relates to the combination of acompound of the invention together with antiviral agents such asViracept, AZT, aciclovir and famciclovir, and antisepsis compounds suchas Valant.

The present invention still further relates to the combination of acompound of the invention together with cardiovascular agents such ascalcium channel blockers, lipid lowering agents such as statins,fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptorantagonists and platelet aggregation inhibitors.

The present invention still further relates to the combination of acompound of the invention together with CNS agents such asantidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine andrasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopaminereuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamineagonists and inhibitors of neuronal nitric oxide synthase), andanti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,propentofylline or metryfonate.

The present invention still further relates to the combination of acompound of the invention together with (i) tryptase inhibitors; (ii)platelet activating factor (PAF) antagonists; (iii) interleukinconverting enzyme (ICE) inhibitors; (iv) IMPDH inhibitors; (v) adhesionmolecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii)MAP kinase inhibitors; (viii) glucose-6 phosphate dehydrogenaseinhibitors; (ix) kinin-B.sub1.- and B.sub2.-receptor antagonists; (x)anti-gout agents, e.g., colchicine; (xi) xanthine oxidase inhibitors,e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues;(xiv) transforming growth factor (TGFβ); (xv) platelet-derived growthfactor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblastgrowth factor (bFGF); (xvii) granulocyte macrophage colony stimulatingfactor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK.sub1. andNK.sub3. receptor antagonists selected from the group consisting ofNKP-608C; SB-233412 (talnetant); and D-4418; (xx) elastase inhibitorsselected from the group consisting of UT-77 and ZD-0892; (xxi) TNFδconverting enzyme inhibitors (TACE); (xxii) induced nitric oxidesynthase inhibitors (iNOS) or (xxiii) chemoattractantreceptor-homologous molecule expressed on TH2 cells, (CRTH2antagonists).

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene, lasofoxifeneor fosomax and immunosuppressant agents such as FK-506, rapamycin,cyclosporine, azathioprine, and methotrexate.

The compounds of the invention may also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib,valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticulartherapies such as corticosteroids and hyaluronic acids such as hyalganand synvisc and P2X7 receptor antagonists.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of cancer. Suitable agentsto be used in combination include:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as alkylating agents (for example    cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside, hydroxyurea, gemcitabine and paclitaxel (Taxol®);    antitumour antibiotics (for example anthracyclines like adriamycin,    bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,    mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for    example vinca alkaloids like vincristine, vinblastine, vindesine and    vinorelbine and taxoids like taxol and taxotere); and topoisomerase    inhibitors (for example epipodophyllotoxins like etoposide and    teniposide, amsacrine, topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    oestrogen receptor down regulators (for example fulvestrant),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) Agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors like marimastat and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine/threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, (for example the anti-vascular    endothelial cell growth factor antibody bevacizumab [Avastin™],    compounds such as those disclosed in International Patent    Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)    and compounds that work by other mechanisms (for example linomide,    inhibitors of integrin αvβ3 function and angiostatin);-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and    WO02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (viii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (ix) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.    Pharmacological Data    Ligand Binding Assay

[¹²⁵I]IL-8 (human, recombinant) was purchased from Amersham, U.K. with aspecific activity of 2,000 Ci/mmol. All other chemicals were ofanalytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells(human embryo kidney 293 cells ECACC No. 85120602) (Lee et al. (1992) J.Biol. Chem. 267 pp16283-16291). hrCXCR2 cDNA was amplified and clonedfrom human neutrophil mRNA. The DNA was cloned into PCRScript(Stratagene) and clones were identified using DNA. The coding sequencewas sub-cloned into the eukauyotic expression vector RcCMV (Invitrogen).Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfectedinto HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of thehighest expressing clone were harvested in phosphate-buffered salinecontaining 0.2% (w/v) ethylenediaminetetraacetic acid (EDTA) andcentrifuged (200 g, 5 min.). The cell pellet was resuspended in ice coldhomogenisation buffer [10 mM HEPES (pH 7.4), 1 mM dithiothreitol, 1 mMEDTA and a panel of protease inhibitors (1 mM phenyl methyl sulphonylfluoride, 2 μg/ml soybean trypsin inhibitor, 3 mM benzamidine, 0.5 μg/mlleupeptin and 100 μg/ml bacitracin)] and the cells left to swell for 10minutes. The cell preparation was disrupted using a hand held glassmortar/PTFE pestle homogeniser and cell membranes harvested bycentrifugation (45 minutes, 100,000 g, 4° C.). The membrane preparationwas stored at −70° C. in homogenisation buffer supplemented withTyrode's salt solution (137 mM NaCl, 2.7 mM KCl, 0.4 mM NaH₂PO₄), 0.1%(w/v) gelatin and 10% (v/v) glycerol.

All assays were performed in a 96-well MultiScreen 0.45 μm filtrationplates (Millipore, U.K.). Each assay contained ˜50 pM [¹²⁵I]IL-8 andmembranes (equivalent to ˜200,000 cells) in assay buffer [Tyrode's saltsolution supplemented with 10 mM HEPES (pH 7.4), 1.8 mM CaCl₂, 1 mMMgCl₂, 0.125 mg/ml bacitracin and 0.1% (w/v) gelatin]. In addition, acompound of formula (I) according to the Examples was pre-dissolved inDMSO and added to reach a final concentration of 1% (v/v) DMSO. Theassay was initiated with the addition of membranes and after 1.5 hoursat room temperature the membranes were harvested by filtration using aMillipore MultiScreen vacuum manifold and washed twice with assay buffer(without bacitracin). The backing plate was removed from the MultiScreenplate assembly, the filters dried at room temperature, punched out andthen counted on a Cobra γ-counter.

The compounds of formula (I) according to the Examples 1-34 were foundto have pIC₅₀ values of greater than (>) 5.5. For example, Examples 3,26 and 33 were found to have pIC₅₀ values of 6.10, 7.00 and 7.50respectively.

Intracellular Calcium Mobilisation Assay

Human neutrophils were prepared from EDTA-treated peripheral blood, aspreviously described (Baly et al. (1997) Methods in Enzymology 287pp70-72), in storage buffer [Tyrode's salt solution (137 mM NaCl, 2.7 mMKCl, 0.4 mM NaH₂PO₄) supplemented with 5.7 mM glucose and 10 mM HEPES(pH 7.4)].

The chemokine GROδ (human, recombinant) was purchased from R&D Systems(Abingdon, U.K.). All other chemicals were of analytical grade. Changesin intracellular free calcium were measured fluorometrically by loadingneutrophils with the calcium sensitive fluorescent dye, fluo-3, asdescribed previously (Merritt et al. (1990) Biochem. J. 269, pp513-519).Cells were loaded for 1 hour at 37° C. in loading buffer (storage bufferwith 0.1% (w/v) gelatin) containing 5 μM fluo-3 AM ester, washed withloading buffer and then resuspended in Tyrode's salt solutionsupplemented with 5.7 mM glucose, 0.1% (w/v) bovine serum albumin (BSA),1.8 mM CaCl₂ and 1 mM MgCl₂. The cells were pipetted into black walled,clear bottom, 96 well micro plates (Costar, Boston, U.S.A) andcentrifuged (200 g, 5 minutes, room temperature).

A compound of formula (I) according to the Examples was pre-dissolved inDMSO and added to a final concentration of 0.1% (v/v) DMSO. Assays wereinitiated by the addition of an A₅₀ concentration of GROδ and thetransient increase in fluo-3 fluorescence (δ_(Ex)=490 nm and δ_(Em)=520nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader,Molecular Devices, Sunnyvale, U.S.A.).

The compounds of formula (I) according to the Examples were tested andfound to be antagonists of the CXCR2 receptor in human neutrophils.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

-   -   (i) when given Nuclear Magnetic Resonance (NMR) spectra were        measured on a Varian Unity Inova 300 or 400 MHz spectrometer. ¹H        NMR data is quoted in the form of delta values for major        diagnostic protons, given in parts per million (ppm) relative to        tetramethylsilane (TMS) as an internal standard;    -   (ii) Mass Spectrometry (MS) spectra were measured on a Finnigan        Mat SSQ7000 or Micromass Platform spectrometer.    -   (iii) the title and sub-titled compounds of the examples and        methods were named using the ACD/Name program (version 4.55)        from Advanced Chemical Development Inc, Canada;    -   (iv) Normal phase column chromatography and normal phase HPLC        was conducted using a silica column. Reverse Phase High pressure        liquid chromatography (HPLC) purification was performed using        either a Waters Micromass LCZ with a Waters 600 pump controller,        Waters 2487 detector and Gilson FC024 fraction collector or a        Waters Delta Prep 4000 or a Gilson Auto Purification System,        using a Symmetry, NovaPak or Ex-Terra reverse phase silica        column.    -   (v) The following abbreviations are used:        -   AcOH acetic acid        -   DCM dichloromethane        -   DMF N,N-dimethylformamide        -   EtOAc ethyl acetate        -   MgSO₄ magnesium sulfate        -   THF tetrahydrofuran        -   H₂O water

EXAMPLE 12-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol

1M aqueous sodium hydroxide (6 ml) followed by benzyl bromide (0.71 ml)was added to a solution of the product of Example 1 step i) (1.0 g) inethanol (20 ml). The mixture was stirred for 2 h, the volatiles removedunder reduced pressure and the residue purified by silica gelchromatography (10% methanol/DCM) to yield the title product as a whitesolid. Yield 0.45 g.

MS APCI (+ve) 292 [M+H]⁺

¹H NMR δ_((DMSO)) 7.45-7.20 (5H, m), 6.72 (1H, br, d), 5.0 (1H, br, t),4.76-4.67 (2H, br, m), 4.35 (2H, s), 3.46-3.24 (2H, m), 1.08 (3H, d).

The intermediates for this compound were prepared as follows:

i) 6-{[(1R)-2-hydroxy-1-methylethyl]amino}-2-mercapto-4-pyrimidinol

6-Amino-2-mercapto-4-pyrimidinol (16.1 g), AcOH (14.3 ml) and(R)-Alaninol (39 ml) were heated at 170° C. for 5 h. The mixture wascooled to approximately 50° C., diluted with water (500 ml) and cooledat 0° C. for 20 h. The resulting solid was filtered, washed with waterand dried in vacuo to yield a mixture of subtitle product and startingmaterial (2:1) as a cream coloured solid. Yield 7.2 g.

MS APCI (+ve) 202 [M+H]⁺

Example 22-(Benzylthio)-5-chloro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol

The product of Example 1 (0.5 g) was dissolved in AcOH (10 ml),N-chlorosuccinamide (0.23 g) added and stirred for 3 h. The mixture wasevaporated and purified by silica gel chromatography (5% methanol/DCM)to yield the title product as a white solid. Yield 0.42 g.

MS APCI (+ve) 326 [M+H]⁺

¹H NMR δ_((DMSO)) 12.36 (1H, s), 7.44-7.22 (5H, m), 6.29 (1H, d), 4.79(1H, t), 4.39 (2H, s), 4.25 (1H, m), 3.52-3.32 (2H, m), 1.12 (3H, d).

Example 32-[(3-Chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol

The product of Example 1 step i) (2.0 g) was dissolved in ethanol (40ml), 1M aqueous sodium hydroxide (12 ml) added followed by3-chlorobenzyl bromide (1.6 ml). The mixture was stirred for 2 h, thevolatiles removed under reduced pressure and the residue purified bysilica gel chromatography (10% methanol/DCM) to yield the title productas a white solid. Yield 1.7 g.

MS APCI (+ve) 326 [M+H]⁺

¹H NMR δ_((DMSO)) 11.39 (1H, s), 7.50 (1H, s), 7.42-7.28 (3H, m), 6.77(1H, m), 4.99 (1H, t), 4.34 (2H, s), 3.45-3.24 (3H, m), 1.08 (3H, d)

Example 45-Chloro-2-[(3-chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol

The product of Example 3 (0.22 g) was dissolved in AcOH (10 ml),N-chlorosuccinamide (90 mg) added and stirred for 3 h. The volatileswere removed under reduced pressure and the residue purified by reversephase HPLC with gradient elution in acetonitrile/0.02M ammoniumhydroxide (90% to 50% aqueous phase) to yield the title product as awhite solid. Yield 0.1 g.

MS APCI (+ve) 360 [M+H]⁺

¹H NMR δ_((DMSO)) 10.33 (1H, s), 7.44-7.20 (3H, m), 6.76 (2H, d), 4.78(1H, m), 4.34 (2H, s), 4.23 (1H, m), 3.51-3.23 (2H, m), 1.12 (3H, d).

Example 52-[(3-Chlorobenzyl)thio]-4-hydroxy-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-pyrimidinylthiocyanate

The product of Example 3 (0.5 g), pyridine (0.21 ml) and potassiumthiocyanate (0.6 g) were dissolved in DMF (10 ml) and cooled to 0° C.Bromine (74 μl) was added before the cooling bath was removed and thereaction mixture allowed to warm to room temperature. After 1 h water(50 ml) was added and the mixture extracted with EtOAc (3×30 ml). Thecombined extracts were dried (MgSO₄), filtered, evaporated and purifiedby silica gel chromatography (10% methanol/DCM) to yield the titleproduct as a white solid. Yield 0.3 g.

MS APCI (+ve) 383 [M+H]⁺

¹H NMR δ_((DMSO)) 12.54 (1H, s), 7.49 (1H, s), 7.15 (1H, d), 7.42-7.31(3H, m), 4.82 (1H, m), 4.33 (1H, m), 3.53-3.36 (2H, m), 1.12 (3H, d),4.43 (2H, m).

Example 6N-(2-[(3-Chlorobenzyl)thio]-4-hydroxy-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-pyrimidinyl)methanesulfonamide

The product from Example 6 step i) (0.15 g) was dissolved in methanol(10 ml), 1M aqueous sodium hydroxide (10 ml) added and the mixtureheated at 80° C. for 1 h. The mixture was cooled to room temperature,evaporated to approximately 10 ml and acidified with 2M hydrochloricacid to yield a white precipitate. The solid was filtered off, washedwith water and dried to yield the title product as a white solid. Yield0.11 g.

MS APCI (+ve) 419 [M+H]⁺

¹H NMR δ_((DMSO)) 8.31 (1H, m), 7.43-7.27 (3H, m), 7.49 (1H, s), 6.03(1H, d), 4.80 (1H, m), 4.39 (2H, m), 4.14 (1H, m), 3.48-3.25 (2H, m),2.96 (3H, s), 1.07 (3H, d).

i)2-[(3-Chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-[(methylsulfonyl)amino]4-pyrimidinylmethanesulfonate

The product of Example 3 (0.9 g) was dissolved in AcOH (12 ml) and asolution of-sodium nitrite (0.25 g) in water (2 ml) added dropwise togive a dark blue solution. After 10 min the mixture was evaporated, andazeotroped with ethanol (×2). The residue was dissolved in ethanol (50ml), AcOH (2 ml) added and heated to reflux. Zinc dust (2.0 g) was addedportionwise and the mixture heated at reflux for a further 5 min. Themixture was cooled to room temperature, filtered through celite andevaporated. The residue was dissolved in DMF (10 ml), treated withimidazole (0.63 g) and tert-butyldimethylsilyl chloride (1.35 g) andstirred for 24 h. The reaction was quenched with water, extracted withEtOAc (×3), dried (MgSO₄), filtered and evaporated. The residue wasdiluted in DCM (50 ml) and treated with diisopropylethylamine (4.4 ml)and methanesulfonyl chloride (0.44 ml) for 1 h before H₂O (10 ml) wasadded. The organics were recovered, dried (MgSO₄) and concentrated. Theresidue was dissolved in THF (30 ml), 1M aqueous sodium hydroxide (5 ml)added, stirred for 1 h, acidified with 2M hydrochloric acid and stirredfor a further 1 h. The mixture was adjusted to pH 7 with sodiumbicarbonate, extracted with EtOAc (×3), dried (MgSO₄), filtered andevaporated. The residue was purified by silica gel chromatography (5%methanol/DCM) to yield the subtitle product as a white solid. Yield 0.12g.

MS APCI (+ve) 497 [M+H]⁺

¹H NMR δ_((DMSO)) 12.42 (1H, s), 7.50 (1H, s), 6.21 (1H, d), 7.43-7.32(3H, m), 4.42 (2H, m), 4.26 (1H, m), 3.47 (3H, s), 3.44 (3H, s), 3.43(2H, m), 1.08 (3H, d).

Example 72-[(3-Chlorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol

The product of Example 3 (0.1 g) was dissolved in methanol (10 ml),Selectfluor™ (0.12 g) added and stirred for 20 h. The mixture wasevaporated and purified by silica gel chromatography (5% methanol/DCM)to yield the title product as a white solid. Yield 19 mg.

MS APCI (+ve) 344 [M+H]⁺

¹H NMR δ_((DMSO)) 7.48 (1H, s), 7.40-7.29 (3H, m), 6.65 (1H, t), 4.34(2H, m), 4.13 (1H, m), 3.47-3.28 (2H, m), 1.09 (3H, d).

Example 82-[(2,3-difluorobenzyl)thio]-4-hydroxy-6{[(1S)-2-hdroxy-1-methylethyl]amino}-pyrimidine-5-carbonitrile

To a solution of the product of Example 8 step vi) (0.65 g) in toluene(5 ml) was added water (24 mg) and potassium tert-butoxide (0.15 g) andthe mixture heated at reflux for 3 h. The reaction mixture was allowedto stand at room temperature for 16 h. The volatiles were removed invacuo and the residue treated with methanol (50 ml) and hydrochloricacid (10 ml, 1M). The-reaction mixture was stirred at room temperaturefor 3 h before the volatiles were removed in vacuo and the residue wasneutralised by the addition of saturated sodium bicarbonate solution.This mixture was extracted with EtOAc (2×100 ml), the combined organicswashed with water (2×20 ml), brine (20 ml), dried (MgSO₄) andconcentrated to yield a yellow solid. This material was purified bycolumn chromatography (EtOAc/isohexane (1:1) to EtOAc) to afford thetitle compound as a white solid. Yield 0.17 g.

MS APCI (+ve) 394 [M+CH₃CN]⁺

¹H NMR δ_((DMSO)) 12.63 (1H, s), 7.31-7.41 (3H, m), 7.14-7.22 (1H, m),4.80 (1H, t), 4.41-4.60 (2H, m), 4.10-4.40 (1H, m), 3.35 (2H, m), 1.20(3H, d).

The intermediates for this compound were prepared as follows:

i) 2-[(2,3-difluorobenzyl)thio]pyrimidine-4,6(1H,5H)-dione

Sodium hydroxide (6.1 g) in ethanol (20 ml) and water (20 ml) was addedto a suspension of 4,6-dihydroxy-2-thiopyrimidine in ethanol/water (120ml/120 ml). 2,3-difluorobenzyl bromide (28.4 g) was added dropwise tothis solution. The mixture was heated at 60° C. for 2 h and stirred atroom temperature for 20 h. The solids were filtered and washed withwater (200 ml), isopropanol (20 ml) and dried in vacuo at 40° C. for 24h to yield the subtitle compound. Yield 31.0 g.

MS APCI (+ve) 271 [M+H]⁺

ii) 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine-5-carbaldehyde

DMF (12.9 ml) was added dropwise to phosphorus oxychloride (39.6 ml) at5° C. The resulting slurry was stirred at room temperature for 2 h. Theproduct of Example 8 step i) was added in portions and stirred at roomtemperature for 1 h. The mixture was then heated at 100° C. for 12 h.The residue was concentrated in vacuo and suspended in water/ice (1:1).The solid formed was extracted with EtOAc (2×150 ml). The EtOAc layerswere washed with water (2×100 ml), brine (100 ml) and dried (MgSO₄). Thesolid was filtered and the filtrate concentrated in vacuo to yield ayellow solid. This was purified by column chromatography usingEtOAc/isohexane (1:9) to yield the subtitle compound. Yield 5.0 g.

¹H NMR δ_((CDCl) ₃ ₎ 10.37 (1H, s), 7.21-7.31 (1H, d), 7.00-7.20 (2H,m), 4.48 (2H, s).

4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine-5-carbaldehyde oxime

Hydroxylamine hydrochloride (0.99 g) was added to a slurry of theproduct of Example 8 step ii) (5.0 g) in water (1.34 ml) and AcOH (21ml). This mixture was then heated at 60° C. for 3 h. The reactionmixture was then allowed to come to room temperature and water (20 ml)added before cooling to 0° C. for 1 h and then filtering. The solidobtained was purified by column chromatography eluting with DCM to yieldthe subtitle compound as a white solid. Yield 1.5 g.

MS APCI (+ve) 351 (M+H)⁺

iv) 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine-5-carbonitrile

The product of Example 8 step iii) (1.5 g) in thionyl chloride (50 ml)was heated at reflux for 4 h. The solvent was removed under reducedpressure and the residue taken up in EtOAc (2×50 ml) and concentratedunder reduced pressure to yield the subtitle compound. Yield 1.5 g.

¹H NMR δ_((CDCl) ₃ ₎ 7.20-7.30 (1H, m), 7.26-7.31 (1H, s), 7.00-7.20(2H, m), 4.45 (2H, s).

v)4-chloro-2-[2,3-difluorobenzyl)thio]-6-{[(1S)-2-hydroxy-1-methylethyl]-amino}pyrimidine-5-carbonitrile

(R)-Alaninol (0.96 g) in DMF (5 ml) was added dropwise at 0° C. to asolution of the product of Example 8 step iv) (1.5 g) in DMF (20 ml).The mixture was stirred at room temperature for 30 min and triethylamine(0.45 g) added at 0° C. The mixture was stirred at room temperature for16 h. To the mixture was added water (30 ml) and extracted with EtOAc(2×100 ml). The combined organics were washed with water (2×20 ml),brine (20 ml) and dried (MgSO₄). The solid was filtered and the filtrateconcentrated in vacuo to give a yellow solid. The solid was purified bycolumn chromatography (30% to 50% EtOAc/isohexane) to yield the subtitlecompound as a yellow solid. Yield 1.10 g.

MS APCI (+ve) 371 (M+H)⁺

¹H NMR δ_((DMSO)) 8.03 (1H, d), 7.31-7.4 (2H, m), 7.13-7.20 (1H, m),4.77 (1H, t), 4.44 (2H, d), 4.28-4.40 (1H, m), 3.35-3.50 (2H, m), 1.15(3H, d).

vi)4-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]-6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidine-5-carbonitrile

Imidazole (0.20 g) was added to a solution of the product of Example 8step v) (1.10 g) and tert-butyldimethylsilyl chloride (0.45 g) in DMF(10 ml) at 0° C. This solution was allowed to warm to room temperatureand stirred for 16 h. To this mixture were added imidazole (20 mg) andtert-butyldimethylsilyl chloride (44 mg) and the mixture stirred for 2 hbefore water (50 ml) was added and extracted with EtOAc (2×100 ml). Thecombined organics were washed with water (3×30 ml), brine (30 ml), dried(MgSO₄), filtered and the filtrate evaporated in vacuo to yield a yellowsolid. This was purified by column chromatography (isohexane and thenDCM) to yield the subtitle compound as a yellow oil. Yield 0.90 g.

MS APCI (+ve) 485 (M+H)⁺

Example 95-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol

Sulphuryl chloride (27 μl) was added to a solution of the subtitleproduct of example 9 step ii) (0.1 g) in DMF (1 ml) and the mixturestirred for 1 h. 1 M aqueous sodium hydroxide solution (1 ml) was thenadded and the reaction stirred for a further 2 h. The mixture wasacidified with 1M hydrochloric acid, extracted with EtOAc (2×10 ml),dried (MgSO₄), filtered and the filtrate evaporated in vacuo. Theresidue was purified by column chromatography (5% methanol/DCM) to yieldthe title product as a white solid. Yield 50 mg.

MS APCI (+ve) 362 [M+H]⁺

¹HNMR δ_((DMSO)) 12.53-12.36 (1H, m), 7.41-7.29 (2H, m), 7.18 (1H, m),6.32 (1H, d), 4.79 (1H, t), 4.46 (2H, dd), 4.20 (1H, m), 3.48-3.31 (2H,m), 1.08 (3H, d)

The intermediates for this compound were prepared as follows:

i)2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol

The subtitle product of Example 1 step i) (5.0 g) was dissolved inethanol (100 ml), 1M aqueous sodium hydroxide (27.4 ml) added followedby 2,3-difluorobenzyl bromide (5.7 g). The mixture was stirred for 1 h,the volatiles removed under reduced pressure and the residue purified bycolumn chromatography (5% methanol/DCM) to yield the subtitle product asa white solid. Yield 4.3 g.

MS APCI (+ve) 328 [M+H]⁺

¹H NMR δ_((DMSO)) 7.41-7.28 (2H, m), 7.15 (1H, m), 6.86-6.69 (1H, m),5.10-4.93 (1H, m), 4.71 (1H, t), 4.41 (2H, s), 3.40 (1H, m), 3.34-3.23(2H, m), 1.07 (3H, d)

ii)6-[[(1R)-2-Acetyloxy)-1-methylethyl]amino]-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol

Acetic anhydride (0.9 ml) was added dropwise to a solution of thesubtitle product of Example 9 step i) (2.8 g), pyridine (1.6 ml) andDMAP (0.1 g) in AcOH (30 ml). Two more portions of acetic anhydride (0.9ml) were added and the mixture stirred for 20 h. The volatiles wereremoved under reduced pressure and the residue purified by columnchromatography (5% methanol/DCM) to yield the subtitle product as acolourless oil. Yield 3.0 g.

MS APCI (+ve) 370 [M+H]⁺

¹H NMR δ_((DMSO)) 11.60-11.37 (1H, m), 7.41-7.28 (2H, m), 7.16 (1H, m),7.06-6.95 (1H, m), 5.07 (1H, s), 4.42 (2H, s), 3.96 (2H, d), 1.99 (3H,s), 1.11 (3H, d)

Example 102-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-iodo-4-pyrimidinol

N-iodosuccinamide (0.34 g) was added to a solution of the subtitleproduct from Example 9 step i) (0.5 g) in AcOH (10 ml) and stirred for 2h. The AcOH was evaporated in vacuo and the residue purified by columnchromatography (5% methanol/DCM) to yield the title product as a whitesolid. Yield 0.42 g.

MS APCI (+ve) 453 [M+H]⁺

¹H NMR δ_((DMSO)) 12.42-12.31 (1H, m), 7.40-7.30 (2H, m), 7.18 (1H, m),5.79 (1H, d), 4.91 (1H, t), 4.47 (2H, dd), 4.15 (1H, m), 3.46-3.39 (2H,m), 1.08 (3H, d)

Example 112-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitro-4-pyrimidinol

1M aqueous sodium hydroxide (1 ml) was added to a solution of theproduct from Example 11 step i) in methanol (10 ml) and the mixturestirred for 2 h. The mixture was diluted with water (20 ml) andacidified with 2M hydrochloric acid (2 ml) to give a red precipitate.The solid was filtered off, washed with water and dried to yield thetitle product as a red solid. Yield 0.15 g.

MS APCI (+ve) 453 [M+H]⁺

¹H NMR δ_((DMSO)) 12.77 (1H, s), 9.63 (1H, d), 7.47-7.29 (2H, m), 7.21(1H, m), 5.09 (1H, t), 4.55 (2H, dd), 4.40 (1H, m), 3.49 (2H, m), 1.14(3H, d)

The intermediates for this compound were prepared as follows:

i)6-[[(1R)-2-(Acetyloxy)-1-methylethyl]amino]-2-[[(2,3-difluorophenyl)methyl]thio]-5-nitro-4-pyrimidinol

A 0.5M solution of nitronium tetrafluoroborate in sulpholane (6.9 ml)was added dropwise to a solution of the product from Example 9 step ii)(1.0 g) in acetonitrile (30 ml) and the mixture stirred for 20 h. Theacetonitrile was evaporated in vacuo and the remaining solution dilutedwith water (150 ml) to give a lilac precipitate. The solid was filteredoff, washed with water and dried to yield the subtitle product as alilac solid. Yield 0.85 g.

MS APCI (+ve) 415 [M+H]⁺

¹H NMR δ_((DMSO)) 12.84 (1H, s), 9.47 (1H, d), 7.45-7.29 (2H, m), 7.20(1H, m), 4.70 (1H, m), 4.54 (2H, s), 4.19-4.06 (2H, m), 1.99 (3H, s),1.20 (3H, d)

Example 122-[[(3-Chlorophenyl)methyl]thio]-6-[[(1R)2-hydroxy-1-methylethyl]amino]-5-(1,3,4-thiadiazol-2-ylthio)-4-pyrimidinol

The product of Example 3 (0.12 g), pyridine (50 μl) and1,3,4-thiadiazole-2-thiol (0.18 g) were dissolved in DMF (3 ml) andbromine (18 μl) added dropwise. The reaction mixture was stirred for 1 hbefore being purified directly by reverse phase HPLC (95-75% 0.02Mammonium hydroxide/acetonitrile) to yield the title product as a whitesolid. Yield 0.15 g.

MS APCI (+ve) 442 [M+H]⁺

¹H NMR δ_((DMSO)) 12.47 (1H, s), 9.36 (1H, s), 7.51 (1H, s), 7.43-7.32(3H, m), 7.09 (1H, d), 4.77 (1H, t), 4.45 (2H, dd), 4.31 (1H, m),3.47-3.28 (2H, m), 1.06 (3H, d)

Example 132-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1H-imidazol-2-ylthio)-4-pyrmidinol

The product of Example 9 step i) (0.1 g), pyridine (0.15 ml) and1H-imidazole-2-thiol (0.15 g) were dissolved in DMF (1 ml) and bromine(15 μl) added dropwise. The reaction mixture was stirred for 1 h beforebeing purified directly by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 90 mg.

MS APCI (+ve) 426 [M+H]⁺

¹H NMR δ_((DMSO)) 7.41-7.30 (2H, m), 7.18 (1H, m), 7.02-6.86 (2H, m),6.75 (1H, d), 5.02-4.88 (1H, m), 4.48 (2H, dd), 4.21 (1H, m), 3.45-3.25(2H, m), 1.06 (3H, d)

Example 142-[[(2,3-Difluorophenyl)methyl]thio]-5-[[2-dimethylamino)ethyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and2-(dimethylamino)ethanethiol (85 mg) were dissolved in DMF (0.5 ml) andbromine (7.5 μl) added. The reaction mixture was stirred for 1 h beforebeing purified directly by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 30 mg.

MS APCI (+ve) 431 [M+H]⁺

¹H NMR δ_((DMSO)) 7.42-7.29 (2H, m), 7.18 (1H, m), 6.64 (1H, d),4.96-4.75 (1H, m), 4.45 (2H, dd), 4.17 (1H, m), 3.61-3.22 (2H, m),2.93-2.58 (4H, m), 2.51 (6H, s), 1.10 (3H, d)

Example 151-[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]-4(1H)-pyridinethione

The product of Example 9 step i) (50 mg), pyridine (75 μl) and4-pyridinethiol (75 mg) were dissolved in DMF (0.5 ml) and bromine (7.5μl) added. The reaction mixture was stirred for 1 h before beingpurified directly by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 5 mg.

MS APCI (+ve) 437 [M+H]⁺

¹H NMR δ_((DMSO)) 8.35 (2H, d), 7.42-7.34 (2H, m), 7.26 (1H, m), 7.14(2H, d), 7.02 (1H, d), 4.54 (2H, dd), 4.51 (1H, m), 3.79-3.65 (2H, m),1.06 (3H, d)

Example 162-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(4-pyridinylthio)-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and4-pyridinethiol (75 mg) were dissolved in DMF (0.5 ml) and bromine (7.5μl) added. The reaction mixture was stirred for 1 h before beingpurified directly by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 31 mg.

MS APCI (+ve) 437 [M+H]⁺

¹H NMR δ_((DMSO)) 8.28 (2H, d), 7.40-7.30 (2H, m), 7.18 (1H, m), 6.98(2H, d), 4.75 (1H, m), 4.44 (2H, dd), 4.15 (1H, m), 3.40-3.25 (2H, m),1.01 (3H, d)

Example 172-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1H-1,2,4-triazol-3-ylthio)-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and1H-1,2,4-triazole-3-thiol (61 mg) were dissolved in DMF (0.5 ml) andbromine (7.5 μl) added. The reaction mixture was stirred for 1 h beforebeing purified directly by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 32 mg.

MS APCI (+ve) 427 [M+H]⁺

¹H NMR δ_((DMSO)) 12.44-12.06 (1H, m), 7.41-7.32 (2H, m), 7.20 (1H, m),6.68-6.49 (1H, m), 4.87-4.73 (1H, m), 4.50 (2H, dd), 4.23 (1H, m),3.45-3.26 (2H, m), 1.04 (3H, d)

Example 182-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and4-methyl-4H-1,2,4-triazole-3-thiol (69 mg) were dissolved in DMF (0.5ml) and bromine (7.5 μl) added. The reaction mixture was stirred for 1 hbefore being purified directly by reverse phase HPLC (95-25% 0.02Mammonium hydroxide/acetonitrile) to yield the title product as a whitesolid. Yield 42 mg.

MS APCI (+ve) 441 [M+H]⁺

¹H NMR δ_((DMSO)) 12.33 (1H, s), 8.51 (1H, s), 7.41-7.28 (2H, m), 7.18(1H, m), 6.75 (1H, d), 4.88 (1H, t), 4.47 (2H, dd), 4.19 (1H, m),3.47-3.26 (2H, m), 1.07 (3H, d)

Example 195-[(5-Amino-4H-1,2,4-triazol-3-yl)thio]-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and5-amino-4H-1,2,4-triazole-3-thiol (70 mg) were dissolved in DMF (0.5 ml)and bromine (7.5 μl) added. The reaction mixture was stirred for 1 hbefore being purified directly by reverse phase HPLC (95-25% 0.02Mammonium hydroxide/acetonitrile) to yield the title product as a whitesolid. Yield 23 mg.

MS APCI (+ve) 442 [M+H]⁺

¹HNMR δ_((DMSO)) 7.43-7.29 (2H, m), 7.19 (1H, m), 6.46 (1H, d),6.06-5.89 (2H, m), 4.83 (1H, t), 4.47 (2H, dd), 4.17 (1H, m), 3.46-3.25(2H, m), 1.04 (3H, d)

Example 202-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[[5-(4-pyridinyl)-1,3,4-oxadiazol-2-yl]thio]-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and5-(4-pyridinyl)-1,3,4-oxadiazole-2-thiol (50 mg) were dissolved in DMF(0.5 ml) and bromine (7.5 μl) added. The reaction mixture was stirredfor 1 h before being purified directly by reverse phase HPLC (95-25%0.02M ammonium hydroxide/acetonitrile) to yield the title product as awhite solid. Yield 10 mg.

MS APCI (+ve) 505 [M+H]⁺

¹H NMR δ_((DMSO)) 12.49 (1H, s), 8.81 (2H, d), 7.83 (2H, d), 7.43-7.34(2H, m), 7.21 (1H, m), 7.03 (1H, d), 4.75 (1H, t), 4.54 (2H, dd), 4.33(1H, m), 3.47-3.26 (2H, m), 1.06 (3H, d)

Example 21 Ethyl[[2-[[(2,3-difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-AcOH

The product of Example 9 step i) (0.5 g), pyridine (0.75 ml) and5-(4-pyridinyl)-1,3,4-oxadiazole-2-thiol (0.66 ml) were dissolved in DMF(5 ml) and bromine (75 μl) added and stirred for 1 h. The mixture wasquenched with water, extracted with EtOAc (2×30 ml), dried (MgSO₄),filtered and the volatiles removed by evaporation in vacuo. The residuewas purified by silica gel chromatography (5% methanol/EtOAc) to yieldthe title product as a white solid. Yield 0.25 g.

MS APCI (+ve) 446 [M+H]⁺

¹HNMR δ_((DMSO)) 12.22 (1H, s), 7.41-7.29 (2H, m), 7.18 (1H, m), 6.51(1H, d), 4.85 (1H, t), 4.47 (2H, dd), 4.15 (1H, m), 3.98 (2H, q),3.47-3.26 (2H, m), 3.31 (2H, dd), 1.09 (3H, t), 1.08 (3H, d)

Example 222-[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-N-methyl-acetamide

The product of Example 21 (0.1 g) was dissolved in ethanol (10 ml), 40%aqueous methylamine (2 ml) was added and the mixture stirred for 20 h.The volatiles were removed by evaporation in vacuo and the residuepurified by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 0.1 g.

MS APCI (+ve) 431 [M+H]⁺

¹H NMR δ_((DMSO)) 8.27 (1H, s), 7.40-7.29 (2H, m), 7.18 (1H, m), 6.79(1H, d), 4.79 (1H, t), 4.46 (2H, dd), 4.17 (1H, m), 3.47-3.30 (2H, m),3.16 (2H, s), 2.55 (3H, d), 1.08 (3H, d)

Example 232-[[2-[[(2,3-Difluorophenyl)methyl]thio]4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-N-[2-(dimethylamino)ethyl]-acetamide

The product of Example 21 (50 mg) was dissolved in ethanol (10 ml),N,N-dimethyl-1,2-ethanediamine (0.5 ml) was added and the mixturestirred for 48 h. The volatiles were removed by evaporation in vacuo andthe residue purified by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 30 mg.

MS APCI (+ve) 488 [M+H]⁺

¹HNMR δ_((DMSO)) 8.52 (1H, s), 7.39-7.29 (2H, m), 7.16 (1H, m), 6.63(1H, d), 4.90-4.70 (1H, m), 4.43 (2H, dd), 4.13 (1H, m), 3.47-3.25 (2H,m), 3.13 (2H, q), 2.30 (2H, t), 2.16 (2H, s), 1.09 (3H, d)

Example 241-[[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]acetyl]-piperazine

The product of example 21 (50 mg) was dissolved in methanol (10 ml),piperazine (0.5 ml) was added and the mixture heated at 40° C. for 20 h.The volatiles were removed by evaporation in vacuo and the residuepurified by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 20 mg.

MS APCI (+ve) 486 [M+H]⁺

¹HNMR δ_((DMSO)) 7.39-7.29 (2H, m), 7.18 (1H, m), 6.56 (1H, d),4.88-4.77 (1H, m), 4.45 (2H, dd), 4.11 (1H, m), 3.46-3.27 (6H, m), 3.42(2H, s), 2.69-2.53 (4H, m), 1.07 (3H, d)

Example 252-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(4-methyl-2-oxazolyl)thio]-4-pyrimidinol

The product of Example 9 step i) (50 mg), pyridine (75 μl) and4-methyl-2-oxazolethiol (69 mg) were dissolved in DMF (0.5 ml) andbromine (7.5 μl) added. The reaction mixture was stirred for 1 h beforebeing purified directly by reverse phase HPLC (95-25% 0.02M ammoniumhydroxide/acetonitrile) to yield the title product as a white solid.Yield 21 mg.

MS APCI (+ve) 439 [M+H]⁺

¹H NMR δ_((DMSO)) 7.71 (1H, s), 7.49 (1H, s), 7.42-7.30 (3H, m), 4.77(1H, t), 4.38 (2H, dd), 4.22 (1H, m), 3.45-3.24 (2H, m), 2.00 (3H, s),1.05 (3H, d)

Example 262-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(1,2,4-oxadiazol-3-ylmethyl)thio]-4-pyrimidinol

The product of Example 5 (0.2 g) was dissolved in ethanol (10 ml),sodium borohydride (20 mg) added and the reaction stirred for 1 h. 1Msodium hydroxide solution (2 ml) was then added, followed by3-(chloromethyl)-1,2,4-oxadiazole (62 mg). The mixture was stirred for 2h, acidified with 10% hydrochloric acid, extracted with EtOAc (2×20 ml),dried (MgSO₄), filtered and the filtrate evaporated in vacuo. Theresidue was purified by reverse phase HPLC with gradient elution inacetonitrile/0.02M ammonium hydroxide (95% to 25% aqueous phase,Ex-Terra) to yield the title product as a white solid. Yield 20 mg.

MS APCI (+ve) 442 [M+H]⁺

¹H NMR δ_((DMSO)) 12.21 (1H, s), 9.47 (1H, s), 7.41-7.27 (2H, m), 7.18(1H, m), 6.18 (1H, m), 4.79 (1H, t), 4.44 (2H, dd), 4.06 (1H, m), 3.84(2H, dd), 3.38-3.23 (2H, m), 0.94 (3H, d)

Example 272-[(2,3-difluorobenzyl)thio]-4-{[(1R)-1,2-dihydroxyethyl]amino}-6-hydroxypyrimidine-5-carboxamide

To the title product of Example 8 (0.230 g) was added ethanol (5 ml),water (5 ml) and potassium hydroxide (0.50 g). The reaction mixture wasthen heated at reflux for 16 h. To the reaction mixture was added morepotassium hydroxide (1.0 g) at intervals and reaction reflux wascontinued for another 24 h. The reaction mixture was acidified withconcentrated hydrochloric acid and extracted with EtOAc (2×50 ml). Thecombined organic layer was washed with water (2×20 ml), brine (10 ml)and dried (MgSO₄). The solid was filtered and the filtrate evaporated todryness. The material was chromatographed on silica gel eluting withEtOAc to yield the title product as a white solid. Yield 5 mg.

MS APCI (+ve) 371 [M+H]⁺

¹H NMR δ_((DMSO)) 12.35 (1H, bs), 10.55 (1H, bs), 9.10 (1H, bs),7.23-7.40 (2H, m) 7.14-7.22 (1H, m), 7.01 (1H, m), 4.86 (1H, t),4.40-4.50 (2H, dd), 4.15-4.25 (1H, m), 3.30-3.45 (2H, m), 1.08 (3H, d).

Example 282-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-ol

To the title product of Example 8 step vi) (0.25 g) added ethanol (5ml), hydroxylamine hydrochloride (0.11 g) and sodium ethoxide (0.1 g).The reaction mixture was stirred at room temperature for 2 h then heatedat reflux for 16 h. The solvent was evaporated and to the residue wereadded toluene (10 ml), acetic anhydride (50 mg) and triethylamine (0.10g). This mixture was heated at reflux for 2 h. The solvent wasevaporated and the residue taken in methanol (20 ml) and aqueous 1Mhydrochloric acid (10 ml). This was stirred for 30 min before thesolvent was evaporated. The residue was extracted with EtOAc (2×50 ml).The organic layer was washed with water (2×20 ml), brine (10 ml) anddried (MgSO₄). The solid was filtered and the filtrate evaporated todryness. The material was purified by reverse phase HPLC (95-25% 0.02Mammonium hydroxide/acetonitrile) to yield the title product as a whitesolid. Yield 4 mg.

MS APCI (+ve) 410 [M+H]⁺

¹H NMR δ_((CD) ₃ _(OD)) 7.20-7.30 (1H, m) 6.99-7.08 (2H, m), 4.32-4.48(2H+1H, m), 3.4-3.58 (2H, m), 2.51-2.55 (3H, bs), 1.12 (3H, d).

Example 292-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-(1,3-oxazol-5-yl)pyrimidin-4-ol

To the subtitle product of Example 29 step iii) (0.48 g) was addedmethanol (10 ml), p-toluenesulfonylmethyl isocyanide (0.18 g) andpotassium carbonate (0.13 g). The reaction mixture was heated at refluxfor 2 h. The solvent was evaporated and the residue treated withhydrochloric acid (1M, 10 ml) and methanol (30 ml). The reaction wasstirred at room temperature for 10 min. The solvent was evaporated andthe residue extracted with EtOAc (2×50 ml), washed with saturated sodiumcarbonate (10 ml), brine (20 ml) and dried (MgSO₄). The solvent wasevaporated and the residue, diluted in DCM (10 ml), treated withdiethylamine (0.50 g) and tetrakis(triphenylphosphine)palladium (79 mg).The reaction was stirred at room temperature for 1 h before the solventwas evaporated and the residue suspended in aqueous hydrochloric acid(50 ml) and extracted with EtOAc (2×50 ml). The organic layer was washedwith brine (20 ml) and dried (MgSO₄). The solid was filtered and thefiltrate evaporated to dryness to give a blue semi-solid. The residuewas further purified by reverse phase HPLC with gradient elution inacetonitrile/0.02M ammonium hydroxide (95% to 25% aqueous phase,Ex-Terra) to yield the title product as a white solid. Yield 6 mg.

MS APCI (+ve) 395 [M+H]⁺

¹H NMR δ_((CD) ₃ _(OD)) 8.30 (1H, s), 7.58 (1H, s), 7.30-7.41 (1H, m),7.09-7.30 (2H, m) 4.40-4.70 (2H+1H, m), 3.7-3.85 (2H, m), 3.61-3.64 (1H,m), 1.21 (3H, d).

The intermediates for the above compound were prepared as follows:

i)4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]-amino}-pyrimidine-5-carbaldehyde

A solution of (R)-alaninol (1.12 g) in DMF was added dropwise to thesubtitle product of Example 8 step ii) (5.0 g) and triethylamine (2.1ml) at −5° C. The mixture was allowed to come to room temperature andstirred for 1 h. To the mixture was added water (100 ml), the organicsextracted with EtOAc (2×250 ml), the organic layers combined, washedwith water (3×50 ml), brine (2×50 ml) and dried (MgSO₄). The solid wasfiltered and the filtrate evaporated to dryness to give the subtitlecompound as a yellow solid. Yield 6.40 g.

MS APCI (+ve) 374 [M+H]⁺

ii)4-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]-6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidine-5-carbaldehyde

To a solution of the subtitle product of step i) (5.60 g) in DMF wasadded tert-butyldimethylsilyl chloride (2.40 g) at −10° C. in portions.To this mixture was then added imidazole in portions. The mixture wasthen stirred at 0° C. for 2 h before being quenched with excess water.The mixture was then extracted with EtOAc (2×250 ml), the combinedorganics washed with water (3×300 ml) and brine (2×30 ml). The organiclayer was dried (MgSO₄) and solid was filtered. The filtrate wasevaporated to dryness. The residue was purified by column chromatography(10% EtOAc/isohexane) to yield the subtitle compound as a white solid.

Yield 5.57 g.

MS APCI (+ve) 489 [M+H]⁺

¹H NMR δ_((CDCl) ₃ ₎ 7.20-7.25 (1H, m), 6.97-7.10 (2H, m), 4.40 (3H, m),3.61-3.63 (2H, m), 1.21 (3H, d), 0.91 (9H, s), 0.05 (6H, s).

iii)4-(allyloxy)-6-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)amino]-2-[(2,3-difluorobenzyl)thio]pyrimidine-5-carbaldehyde

To the subtitle product of step ii) (1.0 g) in toluene was added allylalcohol (0.23 g), sodium hydroxide (0.16 g) and benzyltriethylammoniumchloride (10 mg). The mixture was stirred at room temperature for 2 hbefore sodium hydroxide solution (10 ml, 1M) was added the organicsextracted with EtOAc (2×50 ml). The combined organics were washed withbrine (20 ml) and dried (MgSO₄). The solid was filtered and the filtrateevaporated to dryness to yield the subtitle compound as a white solid.Yield 1.0 g

MS APCI (+ve) 510 [M+H]⁺

¹HNMR δ_((CDCl) ₃ ₎ 10.14 (1H, s), 9.30 (1H, d), 7.20-7.25 (1H, m),6.96-7.15 (2H, m), 5.96-6.08 (1H, m), 5.33-5.36 (1H, m), 5.24-5.28 (1H,m), 4.85-4.95 (2H, m) 4.38-4.40 (3H, m), 3.60-3.62 (2H, m), 1.21 (3H,d), 0.87 (9H, s), 0.01 (6H, s).

Example 302-[(2,3-difluorobenzyl)thio]-4-{[(1R)-1,2-dihydroxyethyl]amino}-6-hydroxy-N,N-dimethylpyrimidine-5-carboxamide

To the subtitle product of Example 30 step vii) (0.20 g) in toluene (2ml) was added water (13 mg) and potassium tert-butoxide (84 mg). Themixture was then heated at reflux for 3 h before more water (20 mg) andpotassium tert-butoxide (84 mg) were added and heating maintained foranother 1 h. The solvent was evaporated and the residue diluted inmethanol (20 ml) and aqueous hydrochloric acid (5 ml). When the reactionwas complete the volatiles were removed in vacuo and residue diluted inEtOAc (100 ml) and aqueous hydrochloric acid (20 ml). The organic layerwas washed with water (20 ml), brine (20 ml) and dried (MgSO₄). Thesolid was filtered and the filtrate evaporated to dryness to give thecrude product. This residue was purified by reverse phase HPLC withgradient elution in acetonitrile/0.02M ammonium hydroxide (95% to 25%aqueous phase, Ex-Terra) to yield the title product as a white solid.Yield 15 mg.

MS APCI (+ve) 399 [M+H]⁺

¹H NMR δ_((DMSO)) 7.23-7.33 (2H, m) 7.13-7.19 (1H, m), 6.81 (1H, m),4.40-4.58 (2H, m), 4.05-4.21 (1H, m), 3.30-3.45 (2H, m), 2.80 (6H, 2s),1.25 (3H, d).

The intermediates for the above compound were prepared as follows:

i) 2,4,6-trichloropyrimidine-5-carbaldehyde

To phosphorus oxychloride (329 g) at 0° C. was added DMF (44.5 g)dropwise to give a slurry. This was stirred at 20° C. for 2 h andpyrimidine-2,4,6-triol (30 g) added in portions. The mixture was stirredat room temperature for 2 h and then heated at 100° C. for 12 h. Thephosphorus oxychloride was removed in vacuo and the residue poured ontoice. The resulting solid was filtered and washed with water (100 ml).The solid was extracted with EtOAc (3×200 ml). The combined organicswere washed with water (200 ml), brine (100 ml) and dried (MgSO₄). Thesolid was filtered and the solvent evaporated to afford the subtitlecompound as a yellow oil. Yield 20.0 g.

GC-MS 209 [M⁺].

ii) 2,4,6-trichloropyrimidine-5-carbonyl chloride

To the subtitle product of step i) (5.0 g) in dichloroethane (25 ml) wasadded aza-bis-isobutyronitrile (25 mg) and the mixture heated to 60° C.Sulfuryl chloride (3.67 g) was then added and the reaction heated at 75°C. for 4 h. The same amount of aza-bis-isobutyronitrile (4×25 mg) andsulfuryl chloride (4×3.36 g) was added for 4 days on each day interval.The solvent was evaporated to give a yellow oil which was distilledunder reduced pressure to yield the subtitle compound as a yellow oil.Yield 5.8 g.

GC-MS 245 [M⁺].

iii) 2,4,6-trichloro-N,N-dimethylpyrimidine-5-carboxamide

To a solution of the subtitle product of step ii) (2.0 g) in DCM (20 ml)and sodium bicarbonate (1.36 g) in water (20 ml) at 0° C. was addeddimethylamine (1.00 ml, 40% aqueous) dropwise. The reaction mixture wasstirred at room temperature for 2 h before DCM (40 ml) was added and theaqueous layer separated. The organic layer was washed with water (20ml), brine (10 ml) and dried (MgSO₄). The solid was filtered and thesolvent evaporated to dryness under reduced pressure. The residue waspurified by column chromatography (EtOAc/isohexane (1:1)) to yield thesubtitle compound as an off white solid. Yield 1.9 g

MS APCI (+ve) 255 [M+H]⁺

¹H NMR δ_((CDCl) ₃ ₎ 3.18 (3H, s), 2.96 (3H, s).

iv)2,4-dichloro-6-{[(1R)-1,2-dihydroxyethyl]amino}-N,N-dimethylpyrimidine-5-carboxamide

(R)-alaninol (0.46 g) in DMF (20 ml) was added dropwise to the subtitleproduct of step iii) (1.60 g) at −5° C. To this mixture was addedtriethylamine (0.63 g), the mixture allowed to come to room temperatureand stirred for 1 h. To the mixture was added water (60 ml) and EtOAc(2×200 ml). The organic layer was washed With water (3×50 ml), brine (30ml) and dried (MgSO₄). The solid was filtered and the filtrateevaporated to dryness to give a yellow solid. This was chromatographedusing EtOAc as eluent to yield the subtitle compound.

Yield 1.07 g

MS APCI (+ve) 294 [M+H]⁺

¹H NMR δ_((CDCl) ₃ ₎ 5.90-5.97 (1H, m), 4.31-4.40 (1H, m), 3.73-3.77(1H, m), 3.57-3.73 (1H, m), 3.13 (3H, s), 3.03 (3H, s), 1.26 (3H, d).

v)4[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)amino]-2,6-dichloro-N,N-dimethylpyrimidine-5-carboxamide

To a solution of the subtitle product of step iv) (0.50 g) in DMF (10ml) was added tert-butyldimethylsilyl chloride (0.51 g) at −10° C. inportions. To this mixture was then added imidazole in portions. Themixture was then stirred at 0° C. for 1 h and allowed to come to roomtemperature and stirred for 16 h. The mixture was quenched with waterand extracted with EtOAc (2×250 ml). The combined organics were washedwith water (3×20 ml) and brine (3×20 ml), the organic layer dried(MgSO₄) and the solid filtered. The filtrate was evaporated to drynessand the residue chromatographed on silica gel eluting withEtOAc/isohexane (1:1) to yield the subtitle compound as an oil. Yield1.0 g.

MS APCI (+ve) 407 [M+H]⁺

¹H NMR δ_(CDCl) ₃ ₎ 6.00 (1/2H, d), 5.90 (1/2H, d), 4.20-4.40 (1H, m),3.50-3.61 (2H, m), 3.10 (3H, s), 2.97 (3H, s), 1.22-1.28 (3H, m),0.89-0.90 (9H, d), 0.01-0.06 (6H, m).

vi) (3,4-difluorophenyl)methanethiol

Thiourea (5.0 g) was added to a solution of 3,4-difluorobenzyl bromide(13.6 g) in ethanol (100 ml). The mixture was heated at reflux for 3 hbefore removal of the volatiles in vacuo. The crude solid was suspendedin aqueous sodium hydroxide solution (1.6M, 110 ml) and heated at refluxfor 3 h before allowing to cool to room temperature. The reaction wasacidified with concentrated hydrochloric acid and the organics extractedwith ether (200 ml). The organic layer was washed with saturated sodiumbicarbonate solution (2×50 ml), brine (20 ml), dried (MgSO₄), andconcentrated in vacuo to provide the subtitle product as a colourlessoil. Yield 11.1 g

¹H NMR δ_((CDCl) ₃ ₎ 7.00-7.11 (3H, m), 3.78 (2H, d), and 1.90 (1H, t)

vii)4-[((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)amino]-6-chloro-2-[(2,3-difluorobenzyl)thio]-N,N-dimethylpyrimidine-5-carboxamide

To the subtitle product of step v) (0.9 g) in methanol (10 ml) was addedthe subtitle product of step vi) (0.35 g) and triethylamine (0.22 g) at0° C. The mixture was allowed to come to room temperature and stirredthere for 2 days. To the reaction mixture was added more3,4-difluorobenzyl thiol (35 mg) and triethylamine (22 mg). and stirredfor 24 h. The solvent was evaporated and the residue purified by columnchromatography (EtOAc/isohexane (1:1)) to give the subtitle compound asa solid. Yield 0.45 g

MS APCI (+ve) 532 [M+H]⁺

¹H NMR δ_((CDCl) ₃ ₎ 7.25 (1H, m), 6.95-7.10 (2H, m), 5.81 (1/2H, d),5.70 (1/2H, d), 4.30-4.40 (2H, dd), 4.15-4.30 (1H, m), 3.50-3.61 (2H,m), 3.10 (3H, s), 2.97 (3H, s), 1.10-1.20 (3H, m), 0.92 (9H, d),0.01-0.06 (6H, m).

Example 312-[(2,3-difluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-ol

To the subtitle product from Example 9 step i) (0.85 g) in methanol (20ml) was added Selectfluor™ (1.01 g). The mixture was stirred at roomtemperature for 5 days before the solids were filtered and the solventremoved under reduced pressure. The residue was diluted in EtOAc (10 ml)and hydrochloric acid (1M, 20 ml) added and stirred at room temperaturefor 1 h. EtOAc (50 ml) was added and the organic layer was separated andwashed with aqueous hydrochloric acid (2×20 ml), brine (20 ml) and dried(MgSO₄). The solid was filtered and the solvent evaporated to dryness togive yellow solid which was chromatographed eluting with EtOAc to 2%methanol/EtOAc to yield the subtitle compound as a white solid. Yield0.12 g.

MS APCI (+ve) 346 [M+H]⁺

¹H NMR δ_((DMSO)) 7.31-7.37 (2H, m) 7.13-7.19 (1H, m), 6.68 (1H, br. s),4.69 (1H, t), 4.39-4.50 (2H, m), 4.08-4.15 (1H, m), 3.31-3.39 (1H, m),2.29-3.39 (1H, m), 1.07 (3H, d).

Example 322-[(3,4-difluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-ol

To the subtitle product of step i) (0.38 g) in methanol (10 ml) wasadded Selectfluor™ (0.45 g). The mixture was stirred at room temperaturefor 2 days before the solvent was removed under reduced pressure and theresidue stripped with methanol (3×100 ml). The residue was diluted inEtOAc (100 ml) and washed with aqueous hydrochloric acid (1M, 20 ml),water (2×20 ml), brine (20 ml) and dried (MgSO₄). The solid was filteredand solvent evaporated to dryness to give a yellow solid which waschromatographed eluting with EtOAc to 2% methanol/EtOAc to yield thetitle compound as a white solid. Yield 25 mg.

MS APCI (+ve) 346 [M+H]⁺

¹H NMR δ_((DMSO)) 7.45-7.50 (1H, m), 7.35-7.40 (1H, m) 7.27-7.33 (1H,m), 6.65 (1H, br. s), 4.69 (1H, t), 4.29-4.36 (2H, m), 4.08-4.15 (1H,m), 3.40-3.45 (1H, m), 3.32-3.33 (1H, m), 1.07 (3H, d).

Intermediates for this compound were prepared as follows:

i)2-[(3,4-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol

To the subtitle product of Example 1 step i) (5.45 g) was added ethanol(100 ml) and sodium hydroxide (1.30 g, 33 ml) and stirred for 10 minbefore adding 3,4-difluorobenzyl bromide (6.70 g) and stirring for 16 h.The solvent was evaporated and the residue diluted in EtOAc (2×200 ml)and acidified with aqueous hydrochloric acid until pH<4. The organiclayer was washed with brine (40 ml) and dried (MgSO₄). The solid wasfiltered and the filtrate evaporated to dryness. The residue waspurified by silica gel chromatography eluting with EtOAc/methanol (5%)to afford the subtitle product as an oil. Yield 0.38 g

MS APCI (+ve) 328 [M+H]⁺

¹H NMR δ_((DMSO)) 7.48-7.53 (1H, m), 7.30-7.40 (1H, m) 7.27-7.30 (1H,m), 6.77 (1H, br. s), 4.98 (1H, br. s), 4.71 (1H, t), 4.31 (2H, s),3.40-3.45 (1H, m), 3.25-3.29 (1H, m), 1.07 (3H, d).

Example 332-[(3-fluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol

To the subtitle product of step i) in methanol (20 ml) was addedSelectfluor™ (0.69 g). The mixture was stirred at room temperature for 5days. The solvent was filtered and the filtrate evaporated to drynessand the residue chromatographed eluting with EtOAc to 5% methanol/EtOActo yield the title compound as a white solid. Yield 35 mg.

MS APCI (+ve) 328 [M+H]⁺

¹H NMR δ_((DMSO)) 7.31-7.37 (1H, m) 7.23-7.26 (2H, m), 7.05-7.10 (1H,m), 6.65 (1H, br. s), 4.69 (1H, t), 4.31-4.40 (2H, m), 4.08-4.15 (1H,m), 3.40-3.50 (1H, m), 3.36-3.40 (1H, m), 1.07 (3H, d).

Intermediates for this compound were prepared as follows:

i)2-[(3-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol

To the subtitle product of Example 1 step i) (3.12 g) was added ethanol(100 ml) and sodium hydroxide (20 ml, 1M) and stirred for 10 min. Tothis mixture was added 3-fluorobenzyl bromide (2.83 g) and stirred for16 h. The solvent was evaporated and the residue diluted in EtOAc (2×200ml) and acidified with aqueous hydrochloric acid until pH<4. The organiclayer was washed with brine (40 ml) and dried (MgSO₄). The solid wasfiltered and the filtrate evaporated to dryness. The residue waspurified by silica gel chromatography eluting with EtOAc/methanol (5%)to afford the subtitle product as a yellow oil. Yield 0.50 g

MS APCI (+ve) 310 [M+H]⁺

¹H NMR δ_((DMSO)) 7.32-7.40 (1H, m) 7.25-7.27 (2H, m), 7.04-7.09 (1H,m), 6.77 (1H, br. s), 4.71 (1H, t), 4.30-4.40 (2H, m), 3.20-3.45 (2H,m), 1.07 (3H, d).

Example 342-[(4-fluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol

To the subtitle product of step i) (0.55 g) in methanol (10 ml) wasadded Selectfluor™ (0.25 g). The mixture was stirred at room temperaturefor 3 days. The solvent was filtered and the filtrate evaporated todryness. The resulting material was chromatographed eluting with 5%methanol/EtOAc to yield the title compound as a white solid. Yield 15mg.

MS APCI (+ve) 328 [M+H]⁺

¹H NMR δ_((DMSO)) 7.42-7.46 (2H, m) 7.10-7.20 (2H, m), 6.65 (1H, br. s),4.69 (1H, t), 4.31-4.40 (2H, m), 4.10-4.20 (1H, m), 3.40-3.50 (1H, m),3.30-3.40 (1H, m), 1.07 (3H, d).

The intermediate for this compound was prepared as follows.

i)2-[(4-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol

To the subtitle product of Example 1 step i) (3.12 g) added ethanol (100ml) and sodium hydroxide (0.68 g) and stirred for 10 min. To thismixture was added 4-fluorobenzyl bromide (2.83 g) and stirred for 16 h.The solvent was evaporated and the residue diluted in EtOAc (2×200 ml)and acidified with aqueous hydrochloric acid until pH<4. The organiclayer was washed with brine (40 ml) and dried (MgSO₄). The solid wasfiltered and the filtrate evaporated to dryness. The residue waschromatographed over silica gel eluting with 5% methanol/EtOAc to affordthe subtitle product as a yellow oil. Yield 0.20 g

MS APCI (+ve) 310 [M+H]⁺

¹H NMR δ_((DMSO)) 7.43-7.47 (2H, m) 7.10-7.16 (2H, m), 6.77 (1H, br. s),4.95 (1H, br. s), 4.71 (1H, t), 4.33 (2H, s), 3.24-3.45 (2H, m), 1.09(3H, d).

1. A compound of formula (1) or a pharmaceutically acceptable saltthereof:

wherein R¹ is a group selected from C₃₋₇carbocyclyl, C₁₋₈alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; wherein the group is substituted by 1, 2 or3 substituents independently selected from fluoro, nitrile, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, phenyl or heteroaryl; wherein phenyl and heteroaryl areoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl;wherein R² is C₃₋₇carbocyclyl, optionally substituted by 1, 2 or 3substituents independently selected from: (a) fluoro, —OR⁴,—NR⁵R⁶—CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹;(b) a 3-8 membered ring optionally containing 1, 2 or 3 atoms selectedfrom O, S, —NR⁸ and whereby the ring is optionally substituted byC₁₋₃alkyl or fluoro; or (c) phenyl or heteroaryl, each of which isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —NR⁸COR⁹, —SO₂NR⁵R⁶,—NR⁸SO₂R⁹, C₁₋₆alkyl and trifluoromethyl; or R² is a group selected fromC₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl wherein the group is substitutedby 1, 2 or 3 substituents independently selected from hydroxy, amino,C₁₋₆alkoxy, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, N—(C₁₋₆alkyl)-N-(phenyl)amino, N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,N—(C₁₋₆ alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl, —NR⁸COR⁹,—SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹; wherein R³ is hydrogen or R²; R⁴ ishydrogen or a group selected from C₁₋₆alkyl and phenyl, wherein thegroup is optionally substituted by 1 or 2 substituents independentlyselected from halo, phenyl, —OR¹¹ and —NR¹²R¹³; R⁵ and R⁶ areindependently hydrogen or a group selected from C₁₋₆alkyl and phenylwherein the group is optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, phenyl, —OR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶,—NR¹⁵COR¹⁶, —SONR¹⁵R¹⁶ and NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with thenitrogen atom to which they are attached form a 4- to 7-memberedsaturated heterocyclic ring system optionally containing a furtherheteroatom selected from oxygen and nitrogen atoms, which ring systemmay be optionally substituted by 1, 2 or 3 substituents independentlyselected from phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SONR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁₋₆alkyl, optionally substituted by 1 or 2substituents independently selected from halo, —NR¹⁵R¹⁶ and —OR¹⁷groups; R¹⁰ is hydrogen or a group selected from C₁₋₆alkyl or phenyl,wherein the group is optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶; and eachof R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ is independentlyhydrogen, C₁₋₆alkyl or phenyl; X is hydrogen, halo, cyano, nitro,hydroxy, C₁₋₆alkoxy, optionally substituted by 1 or 2 substituentsselected from halo, —OR¹¹ and —NR¹²R¹³, —NR⁵R⁶, —COOR⁷, —CONR⁵R⁶,—NR⁸COR⁹, thio, thiocyano, thio C₁₋₆alkyl, optionally substituted by 1or 2 substituents selected from halo, —OR¹⁷, —COOR⁷, —NR¹⁵R¹⁶, —CONR⁵R⁶,—SO₂R¹⁰, —SO₂NR⁵R⁶—NR⁸SO₂R¹⁰ or a group selected from C₃₋₇carbocyclyl,C₁₋₈alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, wherein the group is optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and—NR⁸SO₂R⁹; or a -phenyl, -heteroaryl, -thiophenyl, -thioheteroaryl,aminoheteroaryl, and thio C₁₋₆alkylheteroaryl group, all of which may beoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁-C₆alkyl, phenyl, heteroaryl ortrifluoromethyl groups.
 2. A compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₈alkylsubstituted by 1, 2 or 3 substituents independently selected from phenylor heteroaryl, wherein phenyl and heteroaryl are optionally substitutedby 1, 2 or 3 substituents independently selected from halo, cyano, —OR⁴,—SR¹⁰, C₁₋₆alkyl and trifluoromethyl.
 3. A compound according to claim 1or a pharmaceutically acceptable salt thereof, wherein R² is C₁₋₈alkylsubstituted by 1, 2 or 3 substituents independently selected fromhydroxy, amino, C₁₋₆alkoxy, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,N—(C₁₋₆alkyl)-N-phenyl)amino, N—C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₆alkyl)carbamoyl, N—(C₁₋₆alkyl)-N-(phenyl)carbamoyl, carboxy,phenoxycarbonyl, —NR⁸COR⁹, —SO₂R¹⁰, —SO₂NR⁵R⁶ and —NR⁸SO₂R⁹; and whereinR³ is hydrogen.
 4. A compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R⁴, R⁵, R⁶, R⁸, R⁹ and R¹⁰ areindependently hydrogen, C₁₋₄alkyl or phenyl.
 5. A compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein X ishydrogen, halo, cyano, nitro, hydroxy, thio, thiocyano, —CONR⁵R⁶, thioC₁₋₆alkyl, optionally substituted by 1 or 2 substituents selected fromhalo, —OR¹⁷, —NR¹⁵R¹⁶, —CONR⁵R⁶, —NR⁸SO₂R¹⁰, C₁₋₈alkyl, optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,—OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ and—NR⁸SO₂R⁹, heteroaryl, thioheteroaryl or thio C₁₋₄alkylheteroaryl all ofwhich may be optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R⁹, C₁₋₆alkyl, ortrifluoromethyl.
 6. A compound according to claim 2 or apharmaceutically acceptable salt thereof, wherein R¹ is benzylsubstituted by 1 or 2 substituents independently selected from fluoro,chloro, bromo, methoxy, methyl, and trifluoromethyl.
 7. A compoundaccording to claim 3 or a pharmaceutically acceptable salt thereof,wherein R² is C₁₋₄alkyl, substituted by 1, 2 or 3 substituentsindependently selected from hydroxy, amino, C₁₋₆alkoxy, C₁₋₆alkylamino,and di(C₁₋₆alkyl)amino; and R³ is hydrogen.
 8. A compound according toclaim 4 or a pharmaceutically acceptable salt thereof, wherein X ishydrogen, fluoro, chloro, bromo, thiocyano, —NR⁸SO₂R⁹, where R⁸ ishydrogen and R⁹ is methyl, -thioimidazolyl, -thiotriazolyl, —CONH₂,—CONMe₂ or cyano.
 9. A compound selected from the group consisting of:2-(Benzylthio)-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol,2-(Benzylthio)-5-chloro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol,2-[(3-Chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol,5-Chloro-2-[(3-chlorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol,2-[(3-Chlorobenzyl)thio]-4-hydroxy-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-pyrimidinylthiocyanate,N-(2-[(3-Chlorobenzyl)thio]-4-hydroxy-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-pyrimidinyl)methanesulfonamide,2-[(3-Chlorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-pyrimidinol,2-[(2,3-difluorobenzyl)thio]-4-hydroxy-6{[(1S)-2-hydroxy-1-methylethyl]amino}pyrimidine-5-carbonitrile,5-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-iodo-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitro-4-pyrimidinol,2-[[(3-Chlorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1,3,4-thiadiazol-2-ylthio)-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1H-imidazol-2-ylthio)-4-pyrmidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-5-[[2-(dimethylamino)ethyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol,1-[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]-4(1H)-pyridinethione,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(4-pyridinylthio)-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-(1H-1,2,4-triazol-3-ylthio)-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-4-pyrimidinol,5-[(5-Amino-4H-1,2,4-triazol-3-yl)thio]-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[[5-(4-pyridinyl)-1,3,4-oxadiazol-2-yl]thio]-4-pyrimidinol,Ethyl[[2-[[(2,3-difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-AcOH,2-[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-N-methyl-acetamide,2-[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]-N-[2-(dimethylamino)ethyl]-acetamide,1-[[[2-[[(2,3-Difluorophenyl)methyl]thio]-4-hydroxy-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-pyrimidinyl]thio]acetyl]-piperazine,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(4-methyl-2-oxazolyl)thio]-4-pyrimidinol,2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-[(1,2,4-oxadiazol-3-ylmethyl)thio]-4-pyrimidinol,2-[(2,3-difluorobenzyl)thio]-4-{[(1R)-1,2-dihydroxyethyl]amino}-6-hydroxypyrimidine-5-carboxamide,2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-ol,2-[(2,3-difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-5-(1,3-oxazol-5-yl)pyrimidin-4-ol,2-[(2,3-difluorobenzyl)thio]-4-{[(1R)-1,2-dihydroxyethyl]amino}-6-hydroxy-N,N-dimethylpyrimidine-5-carboxamide,2-[(2,3-difluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-ol,2-[(3,4-difluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-ol,2-[(3-fluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-ol,or2-[(4-fluorobenzyl)thio]-5-fluoro-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-olor a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound or a pharmaceutically acceptable saltthereof according to claim 1; and a pharmaceutically-acceptable diluentor carrier.
 11. A pharmaceutical composition which comprises a compoundof claim 1, formula (1) or a pharmaceutically acceptable salt thereof,in conjunction with another pharmaceutical agent.